CA2042289C - Taste masking and sustained release coatings for pharmaceuticals - Google Patents
Taste masking and sustained release coatings for pharmaceuticalsInfo
- Publication number
- CA2042289C CA2042289C CA002042289A CA2042289A CA2042289C CA 2042289 C CA2042289 C CA 2042289C CA 002042289 A CA002042289 A CA 002042289A CA 2042289 A CA2042289 A CA 2042289A CA 2042289 C CA2042289 C CA 2042289C
- Authority
- CA
- Canada
- Prior art keywords
- medicament
- cellulose acetate
- coated
- chewable tablet
- coating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
Abstract
Chewable medicament tablets are made from coated granules of a medicament wherein the coating on said granules comprises a blend of cellulose acetate and/or cellulose acetate butyrate and hydroxypropyl cellulose and a process for making such tablets and a method of providing sustained release of medicaments utilizing such coated granules in a tablet.
Description
2 2 ~ ~
TASTE MASKING AND SUSTAINED RELEASE
COATINGS FOR PHARMACEUTICALS
Field of the Invention This invention relates to tablets containing means to mask the taste of active ingredients and/or provide sustained release of such ingredients. More particularly, the means of providing taste masking and/or sustained release of active inqredients are coatings comprising blends of hydroxypropyl cellulose with cellulose acetate and/or cellulose acetate butyrate.
BACKGROUND OF THE INV~N~ION
Orally administered medicaments are given to the patient in many forms, such as liquid solutions, emulsions, or suspensions, or in solid form such as capsules or tablets (as used herein, the term ~tablet~ means any shaped and compressed solid dosage form, including caplets).
Medicaments administered in tablet or capsule form are usually intended to be swallowed whole. Therefore, the often disagreeable taste of the active ingredient need not be taken into account in formulating the medicine, e~cept for the provision of means to prevent the taste from being apparent during the short time that the medicine is in the mouth. Such means may include the provision of an appropriately thin and quickly dissolving coating on the tablet, the use of the gelatin capsule form (the gelatin outer shell of the capsule keeps the active ingredient inside until the capsule has been swallowed), or simply compressing a tablet firmly so that it will not begin to disintegrate during the short time that it is intended to be in the mouth.
Children, older persons, and many other persons have trouble swallowing whole tablets and even capsules. Therefore, in cases where the dosage to be administered cannot be made into a very small tablet or capsule, it is desirable to provide the medicine either in liquid form or in a chewable solid form, in addition to the tablet or capsule that is designed to be swallowed whole. Even where the medicine can be formulated as a liquid, it is desirable also to be able to provide a chewable solid form because it is usually more convenient to carry a supply of tablets with oneself all day than a container of liquid medicine.
A common problem with chewable tablet forms is the often disagreeable taste of the active ingredient which manifests itself during chewing. In some cases, the taste of the active medicament in a tablet can be overpowered by adding flavoring ingredients to the tablet so that when it is chewed the taste of the active ingredient is simply overpowered. For instance, this has been done with children's Aspirin where the dosage is small enough so that the amount of flavoring agents needed to mask the taste of the medicine is not so great that the tablet becomes unreasonably large. A
children's size tablet of acetaminophen (acetyl para-aminophenol or "APAP") iS available commercially wherein the APAP iS present in granules that are coated with ethyl cellulose. A significant proportion of the APAP remains shielded by the coating (and therefore does not contribute to taste) while the tablet is in the mouth, despite some breakage of the ethyl cellulose coating during compression of the tablet and some additional breakage of the coating during chewing. The APAP becomes bioavailable via permeation through the coating (although ethyl cellulose is not Trade-Mark - 3 - ~ 4 ~
soluble ln aqueous flulds, water does permeate through the coatlng) and from the granules whereln the coatlng was broken.
U.S. Patent Serlal No. 4,851,226 (lssued July 25, 1989) dlscloses chewable medlcament tablets whereln the granules of actlve lngredlent are coated wlth a blend of cellulose acetate or cellulose acetate butyrate and polyvlnyl pyrrolldone (PVP).
The present lnventlon ls dlrected to the dlscovery of a coatlng that can be used to coat granules of actlve medlcament and whlch can achleve a better balance between taste masklng and control of bloavallablllty than can be achleved wlth ethyl cellulose or other prevlously known comblnatlons. Further, the coatlng of the lnventlon can provlde a sustalned release coatlng for medlcaments.
SUMMARY OF THE INVENTION
As embodled and fully descrlbed hereln the present inventlon provldes a medlcament coatlng comprlslng a blend of cellulose acetate (CA) and/or cellulose acetate butyrate (CAB) and hydroxypropyl cellulose (HPC). The coatlng provldes excellent taste masklng whlle stlll permlttlng acceptable bloavallablllty of the actlve lngredlent.
Further, the coatlng can provlde for sustalned release of the medicament.
More speclflcally, the lnventlon provldes a chewable tablet of a medlcament comprlslng compressed coated granules, sald coated granules lndlvldually comprlslng medlcament coated wlth from about 5 to about 28% of the total 7.Q4228~
- 3a -dry welght of the coated medlcament granule of a polymer blend of: (a) cellulose acetate, cellulose acetate butyrate and comblnatlons thereof; and (b) hydroxypropyl cellulose whereln the ratlo of cellulose acetate, cellulose acetate butyrate and comblnations thereof to hydroxypropyl cellulose ls in the range of about 97/3 to about 50/50.
In preferred embodiments of the inventlon the coated medlcament ls lncluded ln a chewable tablet comprlslng ~Q4~8Y
coml~ressed irldlvldual particles of medicament particles coated with a blend of CA and/or CAB and HP~.
In further preferred embodiments, ibuprofen partlcles are coated with a blend of CA and~or CAB and HPC and are then compre.ssed into tablet form together with flavorinq agents and other ingredients that are customarily used in making such chewable tablets.
The invention also provides a process of making and methods using the chewable tablets, as well as, a method of using the coated medlcament partlcles for sustalned release of the active lngredlents.
Accordlngly, ln one aspect, the lnventlon provldes a chewable tablet of a medlcament comprlslng compressed coated gr-arlules, sald coated granules lndlvldually comprlslng medlcament coated wlth a polymer blend of: (a) cellulose acetate, cellulose acetate butyrate and comblnatlons thereof;
and (b) hydroxypropyl cellulose.
In another aspect, the inventlon provldes a process of preparing a chewable medicament tablet comprlsing the steps of coatlng medlcament granules wlth a polymer blend of cellulose acetate, cellulose acetate butyrate or a combination thereof and hydroxypropyl cellulose; and forming a chewable tablet by compresslng the coated medlcament ln the presence of exciplents.
In a further aspect, the inventlon provides a method for taste masklng medicaments comprislng coatlng a medlcament composition with a taste masklng effectlve amount of a polymer blend of cellulose acetate, cellulose acetate butyrate, or A
~ n 4 ~ 2 ~ ~
-4a-comblnation thereof and hydroxypropyl cellulose.
In yet another aspect, the lnventlon provldes a method of provldlng sustalned release of a medlcament comprlslng coatlng a medlcament wlth a sustalned release effectlve amount of a polymer blend of cellulose acetate, cellulose acetate butyrate or comblnatlon thereof and hydro~ypropyl cellulose.
DETAILED DESCRIPTION OF THE INVENTION
The lnventlon wlll now be descrlbed speclflcally ln terms of lts most preferred embodlments whlch ls the preparatlon of chewa~le tablets of lbuprofen, a medlcament used ln both over-the-counter preparatlons and ln prescrlption drugs for analgeslc and antlpyretlc purposes. Reference wlll also be made ln detall hereln to other preferred embodlments of the composltlons, processes and methods of the lnventlon.
In the preferred embodlment of the process of the lnventlon, medlcament, preferably lbuprofen ln granular form, ls coated wlth a blend of HPC and CA and/or CAB so that the granules a-e coated wlth the polymer blend. The coated granules, together wlth other lngredlents such as flavorlng agents, extenders,excipients, and the llke, are compressed lnto tablet form. (As used hereln, the term "granule" refers to lndlvldual partlcles or to agglomerates of lndlvldual partlcles of the medlcament.) A hlgh enough proportlon of the coatlng remalns 2 2 ~ 9 effectively intact on the ibuprofen granules throuqh the compression of the tablet and through normal chewing in the mouth to permit effective taste masking of the normally bitter tasting ibuprofen. The term ~effectively intact~ means that the coating remains sufficiently integral to mask the taste or flavor of the medicament detectable through the coating. This taste masking provides a mean to limit the quantity of other flavoring agents in the tablet is not be so large that an escessively large tablet is required to overpower rather than mask the unpleasant flavor of the medicament.
When the coated granules are swallowed, the active medicament becomes bioavailable via permeation through the coating. Permeation can occur through the intact coating as well as through the coating that has become porous through dissolution of the water soluble HPC component of the coating; the CA and CAB components are water insoluble. Permeation also occurs via disintegration of the coating, which is caused in part by chewing, in part by processing of the tablet (compression), and in part by removal of the HPC component of the coating by dissolution.
The coating may be designed so that the medicament is released relatively rapidly or in a sustained release mode, depending on the proportion of coating to medicament in the granules, or the proportion of the CA and/or CAB to HPC in the coating, or their combination. Generally, higher proportions of HPC used in the coating leads to more rapid release of the medicament.
Cellulose acetate and cellulose acetate butyrate are quite water insoluble but are soluble in organic solvents. They can provide good taste masking properties since they do 20~2~9 not dissolve in the mouth and are tough enough to remain effectively intact during processing and normal chewing in the mouth. If used alone, however, a coating of CA and/or CAB would not provide adequate bioavailability of the active ingredient after swallowing the chewed tablet. To provide the reguisite bioavailability, HPC is added. HPC
is a polymer which is soluble in both water and organic solvents. The water solubility of HPC provides the bioavailability of the active medicament in the GI tract via the mechanisms discussed above. The solubility of HPC
in organic solvents permits ready mising with CA or CAB
during the production of the coated granules, since CA and CAB are not very soluble, if at all, in water, and are most conveniently applied from an organic solvent solution. HPC and CA and~or CAB form clear compatible solutions in organic solvents, preferably acetone/methanol mistures, which are suitable for pharmaceutical coating.
The blend of CA and/or CAB and HPC provides the balance needed for good taste masking while being chewed in the mouth, along with either rapid or sustained bioavailability of the active medicament in the GI tract after swallowing.
The HPC and CA and/or CAB blends of the invention have been found to be more versatile than the PVP blends of Julian and Radebaugh discussed earlier. Due to the superior flesibility of HPC polymer as compared to PVP, higher percentages of HPC (up to 50%) can be used than is recommended by Julian and Radebaugh for PVP (3 to 30%).
Higher amounts of the water soluble component HPC
increases the rate and estent of disintegration of the coating thus increasing the porosity of the coating.
Presence of such higher amount of the water soluble component HPC advantageously increases the bioavailability of the coated medicaments.
2~42289 The coating used is preferably a blend containing about 50 to about 95 percent of CA and/or CAB, by weight of the coating, and about 3 to about 50 percent HPC. Within the range indicated, if sustained release of the medicament is desired, a lower proportion of the water soluble HPC may be used. When rapid release of the medicament is desired, a higher proportion of the water soluble HPC is used, i.e.
up to 50 percent. Routine experimentation will suffice to determine the appropriate proportions of the two polymers to use in individual cases, as is more specifically illustrated below. The upper limit of about S0 percent HPC is limited by practical processing considerations.
The tackiness of the coating solution increases in the higher range amounts of HPC and amounts over S0 percent may lead to particle agglomeration during the coating process. Further, the rate of release can be controlled by use of HPC of specific molecular weight, whereby, higher molecular weight HPC leads to a slower release of medicament.
The coated granules may be made by coating the granules of medicament with an organic solvent solution of the polymers in a fluidized bed coating operation. A wide variety of organic solvents may be used to prepàre the organic solvent solution of the coating polymers. For instance, a preferred solvent is acetone-methanol, but other solvent systems may also be used, including methylene chloride-methanol (e.g. 9:1), acetone-ethyl acetate, toluene-ethanol, and others. As a general rule, the proportion of polymer in the solvent solution will be from about 5 to 20 and preferably 8 to lS weight percent for optimal taste masking and rapid release of drug depending upon the specific solvents used and other similar considerations.
-8- ~al~289 The polymers are dissolved in the solvent and the polymer solution is then coated onto ibuprofen or other medicament active ingredient or combination of ingredients granules, using a fluidized bed coater. Air (which may be heated) passes through a bed of the medicament granules to fluidize them, and the solvent solution of the two polymers is sprayed onto the fluidized bed and thereby coats the granules. The air passing through the bed dries the coated granules, so that a dry coated granule is obtained. The coated granules are then used in combination with various e~cipients, flavors, and colors to make a chewable tablet.
The dried coating as thus applied usually constitutes about 5-20% of the total dry weight of the coated ibuprofen granule. The exact proportions of coating to medicament desired for individual cases can be determined by routine experimentation. The amount of coating may be varied in light of the intended application and desired bulk of the products. Chewable tablets can be acceptable in larger sizes than swallowed tablets since chewing will reduce the size of the tablets in the mouth. Further, tablets intended for pediatric use generally comprise reduced dosage amounts and less bulk. Larger proportions of coating may be used to provide a sustained release or better taste formulation.
When two or more medicaments are utilized in a tablet the coatings may be varied to provide a slower release of one medicament over another. This is especially advantageous for dosing a combination of medicaments that are more effectively released in different parts of the digestive tract or are better released separately in the digestive tract to avoid interference with each other or other incompatibility. Further, the same medicament may be ~ ~ 4 ~
g subject to different coating composition and amounts to provide for sustained release of some portion of the medicament and immediate release of another portion of the medicament to achieve an optimal dosing versus time profile. Obtaining such optimal dosing/time profiles depends upon the particular medicaments and medical needs required. The e~act proportions of coating materials used to achieve these profiles can be determined by routine e~perimentation.
While e~act size of the coated granules has not been found to be critical, the coated granules will usually be sized to pass between between about a 10 and 200 mesh sieve screen (U. S. Sieve Series). In the usual case, the coated granules will be sized from about 40 to 60 mesh.
In addition to ibuprofen, any solid medication in need of taste masking can be used in the invention. Illustrative e~amples include aspirin, naprosen, acetaminophen, pseudoephedrine, substantially pure desibuprofen (i.e.
less than 20% of the inactive R-antipode), desibuprofen lysine, cimetidine, ranitidine, nizatidine, psuedoephedrine hydrochloride, chlorpheniramine maleate, de~tromethorphan hydrobromide, diphenhydramine hydrochloride or citrate, destromethorphan, chlorpheniramine, loperimide, simethicone, salts thereof and combinations thereof. Identification of medicaments herein is intended to apply to pharmaceutically acceptable salts thereof as well. Further, the coating of the invention provides a convenient means for providing sustained release of medicaments and for presenting a viable dosage form for combination medicaments which are incompatible before (during storage) or after *Trade-mark -10- ~ Y
administration or for medicaments which are desirably released in the GI tract at various times or in various places thereof.
E2amples The following procedure and Esamples provide esamples of preferred method and materials for practicing the present invention. These Esamples should be considered illustrative only and not limitative of the present invention, An illustrative preferred procedure for preparing the coated granules of medicament in accordance with the invention is the following:
A solution of the coating polymers is prepared in an organic solvent by simply adding the polymers to the solvent with stirring. The medicament, in granular form, is placed in a fluidized bed coater and is fluidized by a flow of warm air. The temperature of the air has not been found to be narrowly critical, and can vary over a wide range, keeping in mind the fact that the temperature should not be high enough to cause decomposition, sintering, or melting of the medicament granules. When coating ibuprofen granules, a temperature of from about 55~ to 75~C is suitable but such temperature ranges will change depending on the medicament being coated. The rate of air flow is adjusted so as to fluidize the granules.
Such flow will vary depending on factors such as the specific equipment used, the size of the charge of granules, the size of the individual granules, the apparent specific gravity of the granules, and other factors that are known to the worker in the arts relating to fluidized bed coating.
-11- 2Q422~9 After the medicament has been fluidized, the polymer solution is sprayed on top of the fluidized bed. The air flow through the bed is continued until the amount of solvent remaining in the coating has been reduced to parts per million levels. The granules are actually dry to the touch within a very short time after the coating solution has been sprayed onto the granules of medicament; a matter of a few seconds in some cases. However, the total drying time required to ensure that the organic solvent content of the coating has been reduced to the level desired may take much longer, depending on the temperature of the air, the size of the batch, and the like. For batches of ibuprofen weighing four to six kilograms, total drying times of the order of one to three hours have been used.
Routine esperimentation will suffice to determine the appropriate air temperatures and total times required in the fluidized bed coaters in individual cases.
The Examples below set forth the ingredients and proportions for typical laboratory scale preparations of coated medicament granules. The materials used are the following:
Ibuprofen - In the form of granules having a particle size of about 60 mesh;
Loperamide (HCl salt) - In the form of granules having a particle size of about 40-80 mesh;
APAP - Acetaminophen USP granules having a particle size of about 170-270 microns;
Famotidine - In the form of granules having a particle size of about 170-270 microns;
-12- 2~228~
De~ibuprofen lysine - substantially pure granules of S-ibuprofen lysine salt with less than 20 and preferably less than 10% of the inactive R-ibuprofen antipode present.
CA - Cellulose acetate NF powder, for e~ample, CA 398-10 or CA-320S available from the Food and Pharmaceutical Products Division of FMC may be used. The CA 398-10 polymer has an acetyl content of about 39.8%, by weight, a hydrosyl content of 3.4%, by weight, a degree of substitution of 2.7, and a solution viscosity of about 38 poises or 10 seconds, determined by ASTM Method D 1343 in the solution described as Formula A, ASTM Method D 871.
According to the manufacturer, the typical weight average molecular weight is 177,000 and the typical number average molecular weight is 58,500. The CA-320-S polymer has an acetyl content of about 32.0%, by weight, a hydroxyl content of about 9.0~, by weight, and a degree of substitution of 2.1. The manufacturer reports a solution viscosity in 90:10 CH2C12:methanol, at 4% (w/w) concentration, of 50 cps. Typical weight average molecular weight is 100,500 and typical number average molecular weight is 63,500, according to the manufacturer. (Viscosities in poises are converted to ASTM seconds equivalent to values obtained under ASTM
Method D 871.);
CAT - Cellulose triacetate powder, CA-435-75S is also available from FMC. This CAT's acetyl content is 43.5 and the solution viscosity is 68 seconds, determined by the "Ball Drop Method~ of ASTM D 1343, using the solution designated ~Formula D~ in Table 2 of ASTM D 871;
CAB - Cellulose acetate butyrate, CAB 171-15S from FMC.
The polymer has a butyryl content of 17 weight percent, an acetyl content of 29.5 weight percent, and a viscosity of 24 cps in a 4 weight percent solution in methylene c~loride:methanol (90:10) one day after solution preparation. The viscosity is taken at about 25~C;
HPC - Hydro~ypropyl cellulose havinq a molecular weight of about 80,000 to about 370,000. Suitable HPC includes those available from Aqualon in the grades known by the tradenames K1UCEL EF, LF, JF or G~.
The term ~total coat~ refers to the proportion of coating to medicament in the coated granule product, ~charge~ to the weight of medicament, "polymer solution~ to the proportion of polymer in the organic solvent solution, and n total batch~ to the welght of medicament plus coating.
E~amples I-X, below, display the identity of medicament(s), coating polymers, organic solvents and organic solvent solutions of coating polymers, and the proportions of all of these materials for typical laboratory scale batches of coated medicament granules for use in the invention in accordance with the preferred procedure for preparing coated granules of medicament as described above.
* Trade-mark - 14 - ~ ~ 4 ~
Esample I
Active - Acetaminophen Form of Active - Granular APAP
with particle size of 170 - 270 microns.
Coating Solution - Cellulose Acetate 398-10/ Klucel LF
in Acetone/Methanol 80/20 at 8-12%
solids.
Note: Klucel LF has a weight average molecular weight of 95,000. Rlu~el EF (Molecular Weight 80,000) can also be used.
Blend Ratio 70/30 to 90/10 (C~/HPC) for taste masking.
85/15 to 97/3 for sustained release.
Coat Level 10-15~~ for taste masking.
1~-28% for sustained release.
EsamPle II
Active - Acetaminopnen Form of Active - Rotogranulated APAP with smooth, approsimately spherical shape. Size of 170 - 270 microns.
Otherwise same as above for I.
*Trade-mark ~ 2 ~ ~ 9 Example III
Active - Famotidine Form of Active - Rotogranulated with a carrier such as lactose which results in a smooth, approsimately spherical shape. Binders such as povidone can be included in the Rotogranulated particles at levels of 1-10%. Same granular size as in I.
Coat Level 7-15% for taste masking.
Otherwise same as above for I.
ExamPle IV
Active - Dexibuprofen lysine (or other salts of ibuprofen such as Sodium Ibuprofen) Form of Active - Rotogranulated particles can include a binder such as Povidone at levels of 1 -10%. Granular size of 170 - 270 microns.
Coat Level: 10 - 18% for taste masking.
-16- 2V~2~8~
Example V
Active - Napro~en Sodium Form of Active - Rotogranulated as in E~ample IV.
Otherwise same as above for IV.
Example VI
Total Coat 12 % w/w Charge 4000 gms ibuprofen Total Polymer 545.45 gms Polymer 1 65 % w/w CA 354.54 gms Polymer 2 10 % w/w CAB 54.55 gms Polymer 3 25% w/w HPC 136.36 gms Polymer Soln 10 % w/w 5454.55 gms Solvent 1 80 % w/w acetone 3927.27 gms Solvent 2 20 % w/w methanol 981.82 gms Total Batch 4545.45 gms -17- ~42289 E2amPle VII
Total Coat 12 % w/w Charge 4000 gms ibuprofen 480 gms pseudoephedrine-Total Polymer S45.45 gms Polymer 160 % w/w CA 327.27 gms Polymer 240 % w/w HPC 218.18 gms Polymer Soln8 % w/w 6818.18 gms Solvent 180 % w/w acetone 5018.18 gms Solvent 220 % w/w methanol 1254.55 gms Total Batch 5025.45 gms ExamPle VIII
Total Coat 12 % w/w Charge 4000 gms APAP
5480 gms pseudoephedrine 32 gms chlorpheniramine 240 gms de~tromethorphan Total Polymer 545.45 gms Polymer 1 70 % w/w CA 381.82 gms Polymer 2 30 % w/w HPC 163.63 gms Polymer Soln 10 % w/w 5454.55 gms Solvent 1 80 % w/w acetone 3927.27 gms Solvent 2 20 % w/w methanol 981.82 gms Total Batch 5297.45 gms -19- ~L22~
Example IX
Total Coat 12 % w/w Charge 4000 gms aspirin Total Polymer 545.45 gms Polymer 185 % w/w CA 463.64 gms Polymer 215 % w/w HPC 81.82 gms Polymer Soln8 % w/w 6818.18 gms Solvent 190 % w/w acetone 5645.45 gms Solvent 210 % w/w ethyl acetate 627.27 gms Total Batch 4545.45 gms Example X
20 Total Coat12 % w/w Charge 4000 gms loperamide HCl Total Polymer 545.45 gms Polymer 180 % w/w CA 436.36 gms Polymer 220 % w/w HPC 109.09 gms Polymer Soln8 % w/w 6818.18 gms Solvent 180 % w/w acetone 5018.18 gms Solvent 220 % w/w methanol1254.55 gms Total Batch 4545.45 gms 20~22~!~
Example XI
Total Coat 12 % w/w Charge 4000 gms APAP
Total Polymer 545.45 gms Polymer 185 % w/w CAB463.64 gms Polymer 215 % w/w HPC81.82 gms Polymer Soln8 % w/w 6818.18 gms Solvent 180 % w/w CH2C12 5018.18 gms Solvent 220 % w/w methanol 1254.55 gms Total Batch 4545.45 gms E2ample XII
Various other medicament combinations are prepared by coating desirable dosage ranges of medicaments cimetidine, ranitidine and nizatidine and combinations of two or more of pseudeuphedrine HCl, chlorpheniramine maleate, de~tromethorphan HBr, diphenhydramine HCl or citrate, acetaminophen, ibuprofen and naproxen in accordance with the procedure and coatings of any of E2amples I-XI
While the use of fluidized bed coating has been described in some detail as one preferred method for making the coated granules that are utilized in the invention, other techniques for making the coated granules may be used.
Such other techniques include various microencapsulation techniques such as coacervation and solvent evaporation.
~ ~ 4 ~
The following e~amples XI-XIV describes preparation of chewable tablets.
E~am~le XIII
The ingredients displayed below, are sieved, dry blended, and compressed by standard procedures into round (disc shaped) chewable tablets, each weighing 1100 milligrams.
The tablets had diameters of 9/16 inch, thicknesses of 0.573 centimeter, and had volumes of 0.919 cubic centimeter. Each tablet contained 200 milligrams of active ibuprofen per tablet, from coated qranules prepared in accordance with the procedure of E~ample 1 containing '5 weight percent coatins in which the proportion of CA:HPC was 85:15~~ w/w. The table below displays the ingredients, mg/tablet, percent, and grams/batch sufficient to make 10,000 tablets.
ComPonent mg/Tablet Percent Gms/Batch mannitol 611.79 64.75 6117.94 AVICEL PH101 71.76 7.59 717.65 aspartame 11.84 1.25 118.41 citric acid (anhyd) 5.74 0.61 57.41 flavor 4.31 0.46 43.06 PROSWEET 2.87 0.30 28.71 Mg stearate 9.33 0.98 93.29 coated ibuprofen227.27 24.05 2272.70 ~Trade-mark 2 ~ ~
The following table displays some typical proportion ranges fo-r the ingredients that were used in Esamples XIII:
Com~onent Ran~e of ProPortions, mannitol 30 - 70 10 aspartame 0.5 - 3 citric acid 0.1 - 2 flavor 0.2 - 2 PROSW-ET 0.1 - 2 mg stearate 0.4 - 2 coated ibuprofen 10 - 50 The functions of the several ingredients and some typical replacements for them are as follows:
Mannitol is a sweetener. It can be replaced by de~trose, fructose, sorbitol, compressible sugar, or lactose;
Avicel PH101 is microcrystalline cellulose. It is used as a tabletting aid, e.g. to impart hardness. It may be replaced with tricalcium phosphate;
Aspartame is an artificial sweeetener. It can be replaced with others such as saccharin;
Citric acid is used as an acidifying agent to enhance the taste. It can be replaced by other acidifying agents such as malic acid;
*Trade-mark 7 1~ 4 ~
The flavoring agent can be any flavoring agents such as vanilla, peppermint, orange, cherry, or spearmint;
Prosweet is another sweetener. It can be replaced with other materials such as saccharin, aspartame, natural sugars; and Magnesium stearate is a lubricant (to lubricate the dye walls and punches used during the tablet compression 10 procedure). It can be replaced by talc, stearic acid, -calcium stearate, zinc stearate, or the like.
The scope of the present invention is not limited by the description, examples and suggested used herein and modifications can be made without departing from the spirit of the invention. For e~ample, other components may be added to the tablets including additional actives, various flavorings, preservatives and other pharmaceutical e~cipients. The present invention may also be used to provide a sustained release and/or chewable form for vitamins, minerals or other nutrients.
Application of the compositions and processes of the present invention for medical and pharmaceutical uses can be accomplished by any clinical, medical and pharmaceutical methods and techniques as are presently and prospectively known to those skilled in the art. Thus it is intended that the present invention cover the modifications and variations of this invention provided that they come within the scope of the appended claims and their equivalents.
*Trade-mark -74~37-5
TASTE MASKING AND SUSTAINED RELEASE
COATINGS FOR PHARMACEUTICALS
Field of the Invention This invention relates to tablets containing means to mask the taste of active ingredients and/or provide sustained release of such ingredients. More particularly, the means of providing taste masking and/or sustained release of active inqredients are coatings comprising blends of hydroxypropyl cellulose with cellulose acetate and/or cellulose acetate butyrate.
BACKGROUND OF THE INV~N~ION
Orally administered medicaments are given to the patient in many forms, such as liquid solutions, emulsions, or suspensions, or in solid form such as capsules or tablets (as used herein, the term ~tablet~ means any shaped and compressed solid dosage form, including caplets).
Medicaments administered in tablet or capsule form are usually intended to be swallowed whole. Therefore, the often disagreeable taste of the active ingredient need not be taken into account in formulating the medicine, e~cept for the provision of means to prevent the taste from being apparent during the short time that the medicine is in the mouth. Such means may include the provision of an appropriately thin and quickly dissolving coating on the tablet, the use of the gelatin capsule form (the gelatin outer shell of the capsule keeps the active ingredient inside until the capsule has been swallowed), or simply compressing a tablet firmly so that it will not begin to disintegrate during the short time that it is intended to be in the mouth.
Children, older persons, and many other persons have trouble swallowing whole tablets and even capsules. Therefore, in cases where the dosage to be administered cannot be made into a very small tablet or capsule, it is desirable to provide the medicine either in liquid form or in a chewable solid form, in addition to the tablet or capsule that is designed to be swallowed whole. Even where the medicine can be formulated as a liquid, it is desirable also to be able to provide a chewable solid form because it is usually more convenient to carry a supply of tablets with oneself all day than a container of liquid medicine.
A common problem with chewable tablet forms is the often disagreeable taste of the active ingredient which manifests itself during chewing. In some cases, the taste of the active medicament in a tablet can be overpowered by adding flavoring ingredients to the tablet so that when it is chewed the taste of the active ingredient is simply overpowered. For instance, this has been done with children's Aspirin where the dosage is small enough so that the amount of flavoring agents needed to mask the taste of the medicine is not so great that the tablet becomes unreasonably large. A
children's size tablet of acetaminophen (acetyl para-aminophenol or "APAP") iS available commercially wherein the APAP iS present in granules that are coated with ethyl cellulose. A significant proportion of the APAP remains shielded by the coating (and therefore does not contribute to taste) while the tablet is in the mouth, despite some breakage of the ethyl cellulose coating during compression of the tablet and some additional breakage of the coating during chewing. The APAP becomes bioavailable via permeation through the coating (although ethyl cellulose is not Trade-Mark - 3 - ~ 4 ~
soluble ln aqueous flulds, water does permeate through the coatlng) and from the granules whereln the coatlng was broken.
U.S. Patent Serlal No. 4,851,226 (lssued July 25, 1989) dlscloses chewable medlcament tablets whereln the granules of actlve lngredlent are coated wlth a blend of cellulose acetate or cellulose acetate butyrate and polyvlnyl pyrrolldone (PVP).
The present lnventlon ls dlrected to the dlscovery of a coatlng that can be used to coat granules of actlve medlcament and whlch can achleve a better balance between taste masklng and control of bloavallablllty than can be achleved wlth ethyl cellulose or other prevlously known comblnatlons. Further, the coatlng of the lnventlon can provlde a sustalned release coatlng for medlcaments.
SUMMARY OF THE INVENTION
As embodled and fully descrlbed hereln the present inventlon provldes a medlcament coatlng comprlslng a blend of cellulose acetate (CA) and/or cellulose acetate butyrate (CAB) and hydroxypropyl cellulose (HPC). The coatlng provldes excellent taste masklng whlle stlll permlttlng acceptable bloavallablllty of the actlve lngredlent.
Further, the coatlng can provlde for sustalned release of the medicament.
More speclflcally, the lnventlon provldes a chewable tablet of a medlcament comprlslng compressed coated granules, sald coated granules lndlvldually comprlslng medlcament coated wlth from about 5 to about 28% of the total 7.Q4228~
- 3a -dry welght of the coated medlcament granule of a polymer blend of: (a) cellulose acetate, cellulose acetate butyrate and comblnatlons thereof; and (b) hydroxypropyl cellulose whereln the ratlo of cellulose acetate, cellulose acetate butyrate and comblnations thereof to hydroxypropyl cellulose ls in the range of about 97/3 to about 50/50.
In preferred embodiments of the inventlon the coated medlcament ls lncluded ln a chewable tablet comprlslng ~Q4~8Y
coml~ressed irldlvldual particles of medicament particles coated with a blend of CA and/or CAB and HP~.
In further preferred embodiments, ibuprofen partlcles are coated with a blend of CA and~or CAB and HPC and are then compre.ssed into tablet form together with flavorinq agents and other ingredients that are customarily used in making such chewable tablets.
The invention also provides a process of making and methods using the chewable tablets, as well as, a method of using the coated medlcament partlcles for sustalned release of the active lngredlents.
Accordlngly, ln one aspect, the lnventlon provldes a chewable tablet of a medlcament comprlslng compressed coated gr-arlules, sald coated granules lndlvldually comprlslng medlcament coated wlth a polymer blend of: (a) cellulose acetate, cellulose acetate butyrate and comblnatlons thereof;
and (b) hydroxypropyl cellulose.
In another aspect, the inventlon provldes a process of preparing a chewable medicament tablet comprlsing the steps of coatlng medlcament granules wlth a polymer blend of cellulose acetate, cellulose acetate butyrate or a combination thereof and hydroxypropyl cellulose; and forming a chewable tablet by compresslng the coated medlcament ln the presence of exciplents.
In a further aspect, the inventlon provides a method for taste masklng medicaments comprislng coatlng a medlcament composition with a taste masklng effectlve amount of a polymer blend of cellulose acetate, cellulose acetate butyrate, or A
~ n 4 ~ 2 ~ ~
-4a-comblnation thereof and hydroxypropyl cellulose.
In yet another aspect, the lnventlon provldes a method of provldlng sustalned release of a medlcament comprlslng coatlng a medlcament wlth a sustalned release effectlve amount of a polymer blend of cellulose acetate, cellulose acetate butyrate or comblnatlon thereof and hydro~ypropyl cellulose.
DETAILED DESCRIPTION OF THE INVENTION
The lnventlon wlll now be descrlbed speclflcally ln terms of lts most preferred embodlments whlch ls the preparatlon of chewa~le tablets of lbuprofen, a medlcament used ln both over-the-counter preparatlons and ln prescrlption drugs for analgeslc and antlpyretlc purposes. Reference wlll also be made ln detall hereln to other preferred embodlments of the composltlons, processes and methods of the lnventlon.
In the preferred embodlment of the process of the lnventlon, medlcament, preferably lbuprofen ln granular form, ls coated wlth a blend of HPC and CA and/or CAB so that the granules a-e coated wlth the polymer blend. The coated granules, together wlth other lngredlents such as flavorlng agents, extenders,excipients, and the llke, are compressed lnto tablet form. (As used hereln, the term "granule" refers to lndlvldual partlcles or to agglomerates of lndlvldual partlcles of the medlcament.) A hlgh enough proportlon of the coatlng remalns 2 2 ~ 9 effectively intact on the ibuprofen granules throuqh the compression of the tablet and through normal chewing in the mouth to permit effective taste masking of the normally bitter tasting ibuprofen. The term ~effectively intact~ means that the coating remains sufficiently integral to mask the taste or flavor of the medicament detectable through the coating. This taste masking provides a mean to limit the quantity of other flavoring agents in the tablet is not be so large that an escessively large tablet is required to overpower rather than mask the unpleasant flavor of the medicament.
When the coated granules are swallowed, the active medicament becomes bioavailable via permeation through the coating. Permeation can occur through the intact coating as well as through the coating that has become porous through dissolution of the water soluble HPC component of the coating; the CA and CAB components are water insoluble. Permeation also occurs via disintegration of the coating, which is caused in part by chewing, in part by processing of the tablet (compression), and in part by removal of the HPC component of the coating by dissolution.
The coating may be designed so that the medicament is released relatively rapidly or in a sustained release mode, depending on the proportion of coating to medicament in the granules, or the proportion of the CA and/or CAB to HPC in the coating, or their combination. Generally, higher proportions of HPC used in the coating leads to more rapid release of the medicament.
Cellulose acetate and cellulose acetate butyrate are quite water insoluble but are soluble in organic solvents. They can provide good taste masking properties since they do 20~2~9 not dissolve in the mouth and are tough enough to remain effectively intact during processing and normal chewing in the mouth. If used alone, however, a coating of CA and/or CAB would not provide adequate bioavailability of the active ingredient after swallowing the chewed tablet. To provide the reguisite bioavailability, HPC is added. HPC
is a polymer which is soluble in both water and organic solvents. The water solubility of HPC provides the bioavailability of the active medicament in the GI tract via the mechanisms discussed above. The solubility of HPC
in organic solvents permits ready mising with CA or CAB
during the production of the coated granules, since CA and CAB are not very soluble, if at all, in water, and are most conveniently applied from an organic solvent solution. HPC and CA and~or CAB form clear compatible solutions in organic solvents, preferably acetone/methanol mistures, which are suitable for pharmaceutical coating.
The blend of CA and/or CAB and HPC provides the balance needed for good taste masking while being chewed in the mouth, along with either rapid or sustained bioavailability of the active medicament in the GI tract after swallowing.
The HPC and CA and/or CAB blends of the invention have been found to be more versatile than the PVP blends of Julian and Radebaugh discussed earlier. Due to the superior flesibility of HPC polymer as compared to PVP, higher percentages of HPC (up to 50%) can be used than is recommended by Julian and Radebaugh for PVP (3 to 30%).
Higher amounts of the water soluble component HPC
increases the rate and estent of disintegration of the coating thus increasing the porosity of the coating.
Presence of such higher amount of the water soluble component HPC advantageously increases the bioavailability of the coated medicaments.
2~42289 The coating used is preferably a blend containing about 50 to about 95 percent of CA and/or CAB, by weight of the coating, and about 3 to about 50 percent HPC. Within the range indicated, if sustained release of the medicament is desired, a lower proportion of the water soluble HPC may be used. When rapid release of the medicament is desired, a higher proportion of the water soluble HPC is used, i.e.
up to 50 percent. Routine experimentation will suffice to determine the appropriate proportions of the two polymers to use in individual cases, as is more specifically illustrated below. The upper limit of about S0 percent HPC is limited by practical processing considerations.
The tackiness of the coating solution increases in the higher range amounts of HPC and amounts over S0 percent may lead to particle agglomeration during the coating process. Further, the rate of release can be controlled by use of HPC of specific molecular weight, whereby, higher molecular weight HPC leads to a slower release of medicament.
The coated granules may be made by coating the granules of medicament with an organic solvent solution of the polymers in a fluidized bed coating operation. A wide variety of organic solvents may be used to prepàre the organic solvent solution of the coating polymers. For instance, a preferred solvent is acetone-methanol, but other solvent systems may also be used, including methylene chloride-methanol (e.g. 9:1), acetone-ethyl acetate, toluene-ethanol, and others. As a general rule, the proportion of polymer in the solvent solution will be from about 5 to 20 and preferably 8 to lS weight percent for optimal taste masking and rapid release of drug depending upon the specific solvents used and other similar considerations.
-8- ~al~289 The polymers are dissolved in the solvent and the polymer solution is then coated onto ibuprofen or other medicament active ingredient or combination of ingredients granules, using a fluidized bed coater. Air (which may be heated) passes through a bed of the medicament granules to fluidize them, and the solvent solution of the two polymers is sprayed onto the fluidized bed and thereby coats the granules. The air passing through the bed dries the coated granules, so that a dry coated granule is obtained. The coated granules are then used in combination with various e~cipients, flavors, and colors to make a chewable tablet.
The dried coating as thus applied usually constitutes about 5-20% of the total dry weight of the coated ibuprofen granule. The exact proportions of coating to medicament desired for individual cases can be determined by routine experimentation. The amount of coating may be varied in light of the intended application and desired bulk of the products. Chewable tablets can be acceptable in larger sizes than swallowed tablets since chewing will reduce the size of the tablets in the mouth. Further, tablets intended for pediatric use generally comprise reduced dosage amounts and less bulk. Larger proportions of coating may be used to provide a sustained release or better taste formulation.
When two or more medicaments are utilized in a tablet the coatings may be varied to provide a slower release of one medicament over another. This is especially advantageous for dosing a combination of medicaments that are more effectively released in different parts of the digestive tract or are better released separately in the digestive tract to avoid interference with each other or other incompatibility. Further, the same medicament may be ~ ~ 4 ~
g subject to different coating composition and amounts to provide for sustained release of some portion of the medicament and immediate release of another portion of the medicament to achieve an optimal dosing versus time profile. Obtaining such optimal dosing/time profiles depends upon the particular medicaments and medical needs required. The e~act proportions of coating materials used to achieve these profiles can be determined by routine e~perimentation.
While e~act size of the coated granules has not been found to be critical, the coated granules will usually be sized to pass between between about a 10 and 200 mesh sieve screen (U. S. Sieve Series). In the usual case, the coated granules will be sized from about 40 to 60 mesh.
In addition to ibuprofen, any solid medication in need of taste masking can be used in the invention. Illustrative e~amples include aspirin, naprosen, acetaminophen, pseudoephedrine, substantially pure desibuprofen (i.e.
less than 20% of the inactive R-antipode), desibuprofen lysine, cimetidine, ranitidine, nizatidine, psuedoephedrine hydrochloride, chlorpheniramine maleate, de~tromethorphan hydrobromide, diphenhydramine hydrochloride or citrate, destromethorphan, chlorpheniramine, loperimide, simethicone, salts thereof and combinations thereof. Identification of medicaments herein is intended to apply to pharmaceutically acceptable salts thereof as well. Further, the coating of the invention provides a convenient means for providing sustained release of medicaments and for presenting a viable dosage form for combination medicaments which are incompatible before (during storage) or after *Trade-mark -10- ~ Y
administration or for medicaments which are desirably released in the GI tract at various times or in various places thereof.
E2amples The following procedure and Esamples provide esamples of preferred method and materials for practicing the present invention. These Esamples should be considered illustrative only and not limitative of the present invention, An illustrative preferred procedure for preparing the coated granules of medicament in accordance with the invention is the following:
A solution of the coating polymers is prepared in an organic solvent by simply adding the polymers to the solvent with stirring. The medicament, in granular form, is placed in a fluidized bed coater and is fluidized by a flow of warm air. The temperature of the air has not been found to be narrowly critical, and can vary over a wide range, keeping in mind the fact that the temperature should not be high enough to cause decomposition, sintering, or melting of the medicament granules. When coating ibuprofen granules, a temperature of from about 55~ to 75~C is suitable but such temperature ranges will change depending on the medicament being coated. The rate of air flow is adjusted so as to fluidize the granules.
Such flow will vary depending on factors such as the specific equipment used, the size of the charge of granules, the size of the individual granules, the apparent specific gravity of the granules, and other factors that are known to the worker in the arts relating to fluidized bed coating.
-11- 2Q422~9 After the medicament has been fluidized, the polymer solution is sprayed on top of the fluidized bed. The air flow through the bed is continued until the amount of solvent remaining in the coating has been reduced to parts per million levels. The granules are actually dry to the touch within a very short time after the coating solution has been sprayed onto the granules of medicament; a matter of a few seconds in some cases. However, the total drying time required to ensure that the organic solvent content of the coating has been reduced to the level desired may take much longer, depending on the temperature of the air, the size of the batch, and the like. For batches of ibuprofen weighing four to six kilograms, total drying times of the order of one to three hours have been used.
Routine esperimentation will suffice to determine the appropriate air temperatures and total times required in the fluidized bed coaters in individual cases.
The Examples below set forth the ingredients and proportions for typical laboratory scale preparations of coated medicament granules. The materials used are the following:
Ibuprofen - In the form of granules having a particle size of about 60 mesh;
Loperamide (HCl salt) - In the form of granules having a particle size of about 40-80 mesh;
APAP - Acetaminophen USP granules having a particle size of about 170-270 microns;
Famotidine - In the form of granules having a particle size of about 170-270 microns;
-12- 2~228~
De~ibuprofen lysine - substantially pure granules of S-ibuprofen lysine salt with less than 20 and preferably less than 10% of the inactive R-ibuprofen antipode present.
CA - Cellulose acetate NF powder, for e~ample, CA 398-10 or CA-320S available from the Food and Pharmaceutical Products Division of FMC may be used. The CA 398-10 polymer has an acetyl content of about 39.8%, by weight, a hydrosyl content of 3.4%, by weight, a degree of substitution of 2.7, and a solution viscosity of about 38 poises or 10 seconds, determined by ASTM Method D 1343 in the solution described as Formula A, ASTM Method D 871.
According to the manufacturer, the typical weight average molecular weight is 177,000 and the typical number average molecular weight is 58,500. The CA-320-S polymer has an acetyl content of about 32.0%, by weight, a hydroxyl content of about 9.0~, by weight, and a degree of substitution of 2.1. The manufacturer reports a solution viscosity in 90:10 CH2C12:methanol, at 4% (w/w) concentration, of 50 cps. Typical weight average molecular weight is 100,500 and typical number average molecular weight is 63,500, according to the manufacturer. (Viscosities in poises are converted to ASTM seconds equivalent to values obtained under ASTM
Method D 871.);
CAT - Cellulose triacetate powder, CA-435-75S is also available from FMC. This CAT's acetyl content is 43.5 and the solution viscosity is 68 seconds, determined by the "Ball Drop Method~ of ASTM D 1343, using the solution designated ~Formula D~ in Table 2 of ASTM D 871;
CAB - Cellulose acetate butyrate, CAB 171-15S from FMC.
The polymer has a butyryl content of 17 weight percent, an acetyl content of 29.5 weight percent, and a viscosity of 24 cps in a 4 weight percent solution in methylene c~loride:methanol (90:10) one day after solution preparation. The viscosity is taken at about 25~C;
HPC - Hydro~ypropyl cellulose havinq a molecular weight of about 80,000 to about 370,000. Suitable HPC includes those available from Aqualon in the grades known by the tradenames K1UCEL EF, LF, JF or G~.
The term ~total coat~ refers to the proportion of coating to medicament in the coated granule product, ~charge~ to the weight of medicament, "polymer solution~ to the proportion of polymer in the organic solvent solution, and n total batch~ to the welght of medicament plus coating.
E~amples I-X, below, display the identity of medicament(s), coating polymers, organic solvents and organic solvent solutions of coating polymers, and the proportions of all of these materials for typical laboratory scale batches of coated medicament granules for use in the invention in accordance with the preferred procedure for preparing coated granules of medicament as described above.
* Trade-mark - 14 - ~ ~ 4 ~
Esample I
Active - Acetaminophen Form of Active - Granular APAP
with particle size of 170 - 270 microns.
Coating Solution - Cellulose Acetate 398-10/ Klucel LF
in Acetone/Methanol 80/20 at 8-12%
solids.
Note: Klucel LF has a weight average molecular weight of 95,000. Rlu~el EF (Molecular Weight 80,000) can also be used.
Blend Ratio 70/30 to 90/10 (C~/HPC) for taste masking.
85/15 to 97/3 for sustained release.
Coat Level 10-15~~ for taste masking.
1~-28% for sustained release.
EsamPle II
Active - Acetaminopnen Form of Active - Rotogranulated APAP with smooth, approsimately spherical shape. Size of 170 - 270 microns.
Otherwise same as above for I.
*Trade-mark ~ 2 ~ ~ 9 Example III
Active - Famotidine Form of Active - Rotogranulated with a carrier such as lactose which results in a smooth, approsimately spherical shape. Binders such as povidone can be included in the Rotogranulated particles at levels of 1-10%. Same granular size as in I.
Coat Level 7-15% for taste masking.
Otherwise same as above for I.
ExamPle IV
Active - Dexibuprofen lysine (or other salts of ibuprofen such as Sodium Ibuprofen) Form of Active - Rotogranulated particles can include a binder such as Povidone at levels of 1 -10%. Granular size of 170 - 270 microns.
Coat Level: 10 - 18% for taste masking.
-16- 2V~2~8~
Example V
Active - Napro~en Sodium Form of Active - Rotogranulated as in E~ample IV.
Otherwise same as above for IV.
Example VI
Total Coat 12 % w/w Charge 4000 gms ibuprofen Total Polymer 545.45 gms Polymer 1 65 % w/w CA 354.54 gms Polymer 2 10 % w/w CAB 54.55 gms Polymer 3 25% w/w HPC 136.36 gms Polymer Soln 10 % w/w 5454.55 gms Solvent 1 80 % w/w acetone 3927.27 gms Solvent 2 20 % w/w methanol 981.82 gms Total Batch 4545.45 gms -17- ~42289 E2amPle VII
Total Coat 12 % w/w Charge 4000 gms ibuprofen 480 gms pseudoephedrine-Total Polymer S45.45 gms Polymer 160 % w/w CA 327.27 gms Polymer 240 % w/w HPC 218.18 gms Polymer Soln8 % w/w 6818.18 gms Solvent 180 % w/w acetone 5018.18 gms Solvent 220 % w/w methanol 1254.55 gms Total Batch 5025.45 gms ExamPle VIII
Total Coat 12 % w/w Charge 4000 gms APAP
5480 gms pseudoephedrine 32 gms chlorpheniramine 240 gms de~tromethorphan Total Polymer 545.45 gms Polymer 1 70 % w/w CA 381.82 gms Polymer 2 30 % w/w HPC 163.63 gms Polymer Soln 10 % w/w 5454.55 gms Solvent 1 80 % w/w acetone 3927.27 gms Solvent 2 20 % w/w methanol 981.82 gms Total Batch 5297.45 gms -19- ~L22~
Example IX
Total Coat 12 % w/w Charge 4000 gms aspirin Total Polymer 545.45 gms Polymer 185 % w/w CA 463.64 gms Polymer 215 % w/w HPC 81.82 gms Polymer Soln8 % w/w 6818.18 gms Solvent 190 % w/w acetone 5645.45 gms Solvent 210 % w/w ethyl acetate 627.27 gms Total Batch 4545.45 gms Example X
20 Total Coat12 % w/w Charge 4000 gms loperamide HCl Total Polymer 545.45 gms Polymer 180 % w/w CA 436.36 gms Polymer 220 % w/w HPC 109.09 gms Polymer Soln8 % w/w 6818.18 gms Solvent 180 % w/w acetone 5018.18 gms Solvent 220 % w/w methanol1254.55 gms Total Batch 4545.45 gms 20~22~!~
Example XI
Total Coat 12 % w/w Charge 4000 gms APAP
Total Polymer 545.45 gms Polymer 185 % w/w CAB463.64 gms Polymer 215 % w/w HPC81.82 gms Polymer Soln8 % w/w 6818.18 gms Solvent 180 % w/w CH2C12 5018.18 gms Solvent 220 % w/w methanol 1254.55 gms Total Batch 4545.45 gms E2ample XII
Various other medicament combinations are prepared by coating desirable dosage ranges of medicaments cimetidine, ranitidine and nizatidine and combinations of two or more of pseudeuphedrine HCl, chlorpheniramine maleate, de~tromethorphan HBr, diphenhydramine HCl or citrate, acetaminophen, ibuprofen and naproxen in accordance with the procedure and coatings of any of E2amples I-XI
While the use of fluidized bed coating has been described in some detail as one preferred method for making the coated granules that are utilized in the invention, other techniques for making the coated granules may be used.
Such other techniques include various microencapsulation techniques such as coacervation and solvent evaporation.
~ ~ 4 ~
The following e~amples XI-XIV describes preparation of chewable tablets.
E~am~le XIII
The ingredients displayed below, are sieved, dry blended, and compressed by standard procedures into round (disc shaped) chewable tablets, each weighing 1100 milligrams.
The tablets had diameters of 9/16 inch, thicknesses of 0.573 centimeter, and had volumes of 0.919 cubic centimeter. Each tablet contained 200 milligrams of active ibuprofen per tablet, from coated qranules prepared in accordance with the procedure of E~ample 1 containing '5 weight percent coatins in which the proportion of CA:HPC was 85:15~~ w/w. The table below displays the ingredients, mg/tablet, percent, and grams/batch sufficient to make 10,000 tablets.
ComPonent mg/Tablet Percent Gms/Batch mannitol 611.79 64.75 6117.94 AVICEL PH101 71.76 7.59 717.65 aspartame 11.84 1.25 118.41 citric acid (anhyd) 5.74 0.61 57.41 flavor 4.31 0.46 43.06 PROSWEET 2.87 0.30 28.71 Mg stearate 9.33 0.98 93.29 coated ibuprofen227.27 24.05 2272.70 ~Trade-mark 2 ~ ~
The following table displays some typical proportion ranges fo-r the ingredients that were used in Esamples XIII:
Com~onent Ran~e of ProPortions, mannitol 30 - 70 10 aspartame 0.5 - 3 citric acid 0.1 - 2 flavor 0.2 - 2 PROSW-ET 0.1 - 2 mg stearate 0.4 - 2 coated ibuprofen 10 - 50 The functions of the several ingredients and some typical replacements for them are as follows:
Mannitol is a sweetener. It can be replaced by de~trose, fructose, sorbitol, compressible sugar, or lactose;
Avicel PH101 is microcrystalline cellulose. It is used as a tabletting aid, e.g. to impart hardness. It may be replaced with tricalcium phosphate;
Aspartame is an artificial sweeetener. It can be replaced with others such as saccharin;
Citric acid is used as an acidifying agent to enhance the taste. It can be replaced by other acidifying agents such as malic acid;
*Trade-mark 7 1~ 4 ~
The flavoring agent can be any flavoring agents such as vanilla, peppermint, orange, cherry, or spearmint;
Prosweet is another sweetener. It can be replaced with other materials such as saccharin, aspartame, natural sugars; and Magnesium stearate is a lubricant (to lubricate the dye walls and punches used during the tablet compression 10 procedure). It can be replaced by talc, stearic acid, -calcium stearate, zinc stearate, or the like.
The scope of the present invention is not limited by the description, examples and suggested used herein and modifications can be made without departing from the spirit of the invention. For e~ample, other components may be added to the tablets including additional actives, various flavorings, preservatives and other pharmaceutical e~cipients. The present invention may also be used to provide a sustained release and/or chewable form for vitamins, minerals or other nutrients.
Application of the compositions and processes of the present invention for medical and pharmaceutical uses can be accomplished by any clinical, medical and pharmaceutical methods and techniques as are presently and prospectively known to those skilled in the art. Thus it is intended that the present invention cover the modifications and variations of this invention provided that they come within the scope of the appended claims and their equivalents.
*Trade-mark -74~37-5
Claims (18)
1. A chewable tablet of a medicament comprising compressed coated granules, said coated granules individually comprising medicament coated with from about 5 to about 28%
of the total dry weight of the coated medicament granule of a polymer blend of (a) cellulose acetate, cellulose acetate butyrate and combinations thereof; and (b) hydroxypropyl cellulose wherein the ratio of cellulose acetate, cellulose acetate butyrate and combinations thereof to hydroxypropyl cellulose is in the range of about 97/3 to about 50/50.
of the total dry weight of the coated medicament granule of a polymer blend of (a) cellulose acetate, cellulose acetate butyrate and combinations thereof; and (b) hydroxypropyl cellulose wherein the ratio of cellulose acetate, cellulose acetate butyrate and combinations thereof to hydroxypropyl cellulose is in the range of about 97/3 to about 50/50.
2. The chewable tablet of claim 1 wherein the medicament is selected from the group consisting of ibuprofen, acetaminophen, aspirin , naproxen, pseudoephedrine, dextromethorphan, chlorpheniramine, loperamide, diphenhydramine, famotidine, cimetidine, ranitidine, nizatidine, salts thereof, and combinations thereof.
3. The chewable tablet of claim 1 wherein the polymer blend is intended for sustained release and contains from about 3 to about 15 weight percent of hydroxypropyl cellulose.
4. The chewable tablet of claim 1 wherein the coated granules are intended for sustained release and contain from about 16 to about 28 percent of said polymer blend.
5. The chewable tablet of claim 1 wherein the coated granules are intended for taste mask and contain from about 8 to about 15 weight percent of the polymer blend.
6. The chewable tablet of claim 1 wherein the medicament comprises ibuprofen.
7. The chewable tablet of claim 1 wherein the medicament comprises dexibuprofen lysine.
8. The chewable tablet of claim 1 wherein the medicament comprises a combination of ibuprofen and pseudoephedrine.
9. The chewable tablet of claim 1 wherein the medicament comprises loperamide.
10. The chewable tablet of claim 1 wherein the medicament comprises acetaminophen and diphenhydramine hydrochloride or citrate.
11. The chewable tablet of claim 1, wherein the medicament comprises a combination of acetaminophen, pseudoephedrine, dextromethorphan and chlorpheniramine.
12. The chewable tablet of claim 1 wherein the medicament is a combination of an analgesic selected from the group consisting of ibuprofen, acetaminophen and aspirin*;
with pseudoephedrine; chlorpheniramine, and dextromethorphan.
with pseudoephedrine; chlorpheniramine, and dextromethorphan.
13. A process of preparing a chewable medicament tablet comprising the steps of:
coating medicament granules with from about 5 to about 28% of the total dry weight of the coated medicament granule with a polymer blend of cellulose acetate, cellulose acetate butyrate or a combination thereof and hydroxypropyl cellulose wherein the ratio of cellulose acetate, cellulose acetate butyrate and combinations thereof to hydroxypropyl cellulose is in the range of about 97/3 to about 50/50; and forming a chewable tablet by compressing the coated medicament in the presence of excipients.
coating medicament granules with from about 5 to about 28% of the total dry weight of the coated medicament granule with a polymer blend of cellulose acetate, cellulose acetate butyrate or a combination thereof and hydroxypropyl cellulose wherein the ratio of cellulose acetate, cellulose acetate butyrate and combinations thereof to hydroxypropyl cellulose is in the range of about 97/3 to about 50/50; and forming a chewable tablet by compressing the coated medicament in the presence of excipients.
14. A method for taste masking medicaments comprising coating a medicament composition with a taste masking effective amount of from about 5 to about 28% of the total dry weight of the medicament, of a polymer blend of cellulose acetate, cellulose acetate butyrate, or combination thereof and hydroxypropyl cellulose, wherein the ratio of cellulose acetate, cellulose acetate butyrate and combinations thereof to hydroxypropyl cellulose is in the range of about 97/3 to about 50/50.
15. The method of claim 14 wherein the medicament coated is selected from the group consisting of ibuprofen, aspirin*, naproxen, acetaminophen, loperamide, pseudoephedrine, dextromethorphan, chlorpheniramine, diphenhydramine, famotidine, cimetidine, ranitidine, nizatidine, salts thereof, and mixtures thereof.
16. The method of claim 14 wherein the medicament is dexibuprofen lysine.
17. A method of providing sustained release of a medicament comprising coating a medicament with a sustained release effective amount of from about 5 to about 28% of the total dry weight of the medicament, of a polymer blend of cellulose acetate, cellulose acetate butyrate or combination thereof and hydroxypropyl cellulose, wherein the ratio of cellulose acetate, cellulose acetate butyrate and combinations thereof to hydroxypropyl cellulose is in the range of about 97/3 to about 50/50.
18. The method of claim 17 wherein the medicament is selected from the group consisting of ibuprofen, aspirin*, naproxen, acetaminophen, loperamide, pseudoephedrine, dextromethorphan, chlorpheniramine, diphenhydramine, famotidine, cimetidine, ranitidine, nizatidine, salts thereof, and mixtures thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/528,003 US5075114A (en) | 1990-05-23 | 1990-05-23 | Taste masking and sustained release coatings for pharmaceuticals |
| US528,003 | 1990-05-23 | ||
| IN325CA1991 IN172428B (en) | 1990-05-23 | 1991-04-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2042289A1 CA2042289A1 (en) | 1991-11-24 |
| CA2042289C true CA2042289C (en) | 1998-12-08 |
Family
ID=26324259
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002042289A Expired - Lifetime CA2042289C (en) | 1990-05-23 | 1991-05-10 | Taste masking and sustained release coatings for pharmaceuticals |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5075114A (en) |
| EP (1) | EP0459695B1 (en) |
| JP (1) | JP3157190B2 (en) |
| AU (1) | AU639334B2 (en) |
| CA (1) | CA2042289C (en) |
| ES (1) | ES2073677T3 (en) |
| GR (1) | GR1002092B (en) |
| IE (1) | IE67062B1 (en) |
| IN (1) | IN172428B (en) |
| NZ (1) | NZ238131A (en) |
| PT (1) | PT97739B (en) |
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| TW202337326A (en) | 2021-12-17 | 2023-10-01 | 美商紐翠魁斯特有限責任公司 | Methods of improving the nutritional status of immune stressed animals |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK150008C (en) * | 1981-11-20 | 1987-05-25 | Benzon As Alfred | PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL ORAL POLYDEPOT PREPARATION |
| US4643892A (en) * | 1983-07-20 | 1987-02-17 | Warner-Lambert Company | Magnesium trisilicate suitable for preparation of medicament adsorbates of analgesics |
| US4894233A (en) * | 1984-10-05 | 1990-01-16 | Sharma Shri C | Novel drug delivery system for decongestants |
| IE58110B1 (en) * | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
| GB8618811D0 (en) * | 1986-08-01 | 1986-09-10 | Approved Prescription Services | Sustained release ibuprofen formulation |
| US4800087A (en) * | 1986-11-24 | 1989-01-24 | Mehta Atul M | Taste-masked pharmaceutical compositions |
| US4835187A (en) * | 1987-06-15 | 1989-05-30 | American Home Products Corporation | Spray dried ibuprofen |
| US4915949A (en) * | 1987-07-13 | 1990-04-10 | Alza Corporation | Dispenser with movable matrix comprising a plurality of tiny pills |
| US4915953A (en) * | 1987-09-03 | 1990-04-10 | Alza Corporation | Dosage form for delivering acetaminophen or phenylpropanolamine |
| US4837031A (en) * | 1987-09-17 | 1989-06-06 | Mallinckrodt, Inc. | Compositions containing ibuprofen |
| US4851226A (en) * | 1987-11-16 | 1989-07-25 | Mcneil Consumer Products Company | Chewable medicament tablet containing means for taste masking |
| NZ226822A (en) * | 1987-11-16 | 1990-03-27 | Mcneil Consumer Prod | Chewable medicament tablet containing means for taste masking |
| US4835188A (en) * | 1987-12-08 | 1989-05-30 | American Home Products Corporation | Spray dried ibuprofen |
-
1990
- 1990-05-23 US US07/528,003 patent/US5075114A/en not_active Expired - Lifetime
-
1991
- 1991-04-29 IN IN325CA1991 patent/IN172428B/en unknown
- 1991-05-10 CA CA002042289A patent/CA2042289C/en not_active Expired - Lifetime
- 1991-05-10 GR GR910100204A patent/GR1002092B/en not_active IP Right Cessation
- 1991-05-13 NZ NZ238131A patent/NZ238131A/en unknown
- 1991-05-21 AU AU77234/91A patent/AU639334B2/en not_active Expired
- 1991-05-21 JP JP14418391A patent/JP3157190B2/en not_active Expired - Lifetime
- 1991-05-22 IE IE175291A patent/IE67062B1/en not_active IP Right Cessation
- 1991-05-22 EP EP91304631A patent/EP0459695B1/en not_active Expired - Lifetime
- 1991-05-22 PT PT97739A patent/PT97739B/en not_active IP Right Cessation
- 1991-05-22 ES ES91304631T patent/ES2073677T3/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| US5075114A (en) | 1991-12-24 |
| IE67062B1 (en) | 1996-02-21 |
| GR910100204A (en) | 1992-07-30 |
| GR1002092B (en) | 1995-12-28 |
| IE911752A1 (en) | 1991-12-04 |
| EP0459695B1 (en) | 1995-03-15 |
| EP0459695A1 (en) | 1991-12-04 |
| ES2073677T3 (en) | 1995-08-16 |
| AU7723491A (en) | 1991-11-28 |
| CA2042289A1 (en) | 1991-11-24 |
| IN172428B (en) | 1993-07-24 |
| AU639334B2 (en) | 1993-07-22 |
| PT97739B (en) | 1998-10-30 |
| NZ238131A (en) | 1992-09-25 |
| JP3157190B2 (en) | 2001-04-16 |
| PT97739A (en) | 1992-03-31 |
| JPH06316536A (en) | 1994-11-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |