Sustained release matrix

This invention provides a matrix composition for sustained drug delivery which is comprised of an active agent, a hydrophilic polymer and an enteric polymer. The enteric polymer is impermeable to gastric fluids and aids in retarding drug release in regions of low pH, thus allowing lower levels of hydrophilic polymer to be employed. At the pH range of intestinal fluids, this polymer will dissolve and thereby increase the permeability of the dosage form. This approach is useful in sustaining the release of numerous active agents whose solubility declines as the pH is increased, a characteristic of weakly basic drugs. By responding to changes in physiological pH, these sustained release dosage forms have acceptable performance, in spite of variability in the gastrointestinal transit times of the formulation.

BACKGROUND OF THE INVENTION 
Ideally, a sustained release dosage form should deliver the medicament at a 
constant rate throughout the gastrointestinal tract. With many of the 
delivery systems currently available, this expectation may not be realized 
since many drugs which are weakly acidic or basic exhibit solubility which 
varies in relation to pH. A decline in solubility in response to pH 
fluctuations within the body may result in a decreased release rate if the 
formulation does not respond with an appropriate change in its 
permeability characteristics. 
The use of hydrophilic matrices to provide sustained drug release is known. 
Christenson et al. in U.S. Pat. No. 3,065,143 disclose the use of certain 
hydrophilic gums, including hydroxypropyl methylcelluloses, in the 
preparation of sustained release tablets. Hill in U.S. Pat. No. 3,458,622 
describes the preparation of sustained release tablets using a combination 
of povidone and carbopol. Weiss et al. in U.S. Pat. No. 4,252,786 describe 
a controlled release tablet consisting of a core tablet which was 
identical to the tablet disclosed in Hill, that is, containing an active 
ingredient, povidone, and carbopol. A coating consisting of a hydrophobic 
and a hydrophilic polymer was employed to prevent the initial burst of 
drug release encountered with this tablet. Schor et al. in U.S. Pat. No. 
4,389,393 describe sustained release therapeutic compositions based on 
high molecular weight hydroxypropyl methylcellulose. Guley et al. in U.S. 
Pat. No. 4,309,405 describe a sustained release pharmaceutical composition 
comprising a compressed core, a seal coating surrounding the core and a 
sugar coating surrounding the seal coated core wherein, a) the core 
consists of an active ingredient, at least one pharmaceutically acceptable 
water soluble polymer selected from the group of hydroxypropyl 
methylcellulose, hydroxypropyl cellulose, xanthan gum and karaya gum, and 
at least one pharmaceutically acceptable water insoluble polymer mixture 
selected from the group consisting of ethylcellulose and at least one of 
carboxypolymethylene, hydroxypropyl methylcellulose phthalate and 
hydroxypropyl cellulose, said polymers in an amount of about 30% to 72% by 
weight of the core; b) the seal coating comprises a film coating selected 
from the group consisting of enteric and non-enteric materials and 
mixtures thereof; and c) the sugar coating comprises sugar and a loading 
dose of said drug contained in the core. Dunn in U.S. Pat. Nos. 4,522,804, 
4,521,402 and 4,521,401 describes constant order release solid oral. 
dosage formulations comprising an active ingredient, from about 0.5 to 
6.0% of an acid-retardant or hydrophobic cellulose derivative, from about 
2.5 to 35% of a hydrogenated vegetable oil, from about 1 to 20% of 
carbopol, from about 0.5 to 4.0% of fumed silicon dioxide and from about 
0.4 to 3.0% of a lubricant. 
Conventional hydrogels such as those based on high viscosity hydroxypropyl 
methylcelluloses are known to deliver medicaments at a constant rate 
independent of pH in relation to the hydration, gel viscosity and relative 
permeability of the dosage form. This, however, does not ensure that a 
drug whose solubility varies significantly as a function of pH will be 
delivered at a constant rate throughout the gastrointestinal pH range. 
With these conventional hydrogel formulations, the rate of drug release 
will be directly related to the solubility of the drug. If the drug 
possesses greater solubility in gastric fluids as compared to intestinal 
fluids, a characteristic of many weakly basic active ingredients, one 
would expect the release rate of the matrix to be faster in gastric 
fluids, than when the formulation makes the transition into the small 
intestine where the pH values are reported to be higher. For these 
formulations, if the dosage form is not retained for an adequate time 
period in the stomach, the decrease in drug release rate encountered in 
the intestine might result in incomplete bioavailability and greater 
variability from patient to patient. 
Film coatings are known to have the ability to modify the release pattern 
of a drug once applied to pharmaceutical products. One type of film 
coating, known as an enteric coating, is used to prevent the release of 
drugs in, or protect drugs from, the effects of the gastric environment. 
Enteric coatings are used to delay the release of drugs which are 
inactivated by the stomach contents or which cause gastric irritation. 
The matrix compositions of the present invention differ from existing 
formulations in that the present compositions have been designed to 
respond to increases in pH with a corresponding increase in the 
permeability of the dosage form. This allows the dosage form to release 
the active ingredient at an appropriate rate throughout the 
gastrointestinal tract. 
SUMMARY OF THE INVENTION 
This invention provides a matrix composition comprised of an active agent, 
a hydrophilic polymer, and an enteric polymer which results in a dosage 
form which is responsive to physiological pH changes. More specifically, 
the present invention relates to a sustained release matrix formulation in 
tablet unit dosage form comprising from about 0.1% by weight to about 90% 
by weight of an active agent, from about 5% by weight to about 29% by 
weight of a hydrophilic polymer, and from about 0.5% by weight to about 
25% by weight of an enteric polymer, with the proviso that the total 
weight of the hydrophilic polymer and enteric polymer is less than 30% by 
weight of the formulation. This formulation reacts to an increase in pH 
with a corresponding increase in its permeability and rate of erosion. 
This results in an improved mechanism for the sustained delivery of a 
variety of compounds, especially those whose solubility declines as the pH 
is increased.

DETAILED DESCRIPTION OF THE INVENTION 
Amounts and percentages are described herein as weight units unless 
otherwise stated. 
The present formulation is in the form of a matrix of the ingredients 
comprising the formulation. A matrix, as defined herein, means a 
well-mixed composite of ingredients fixed into shape by tabletting. This 
intimate admixture of ingredients provides sustained release of the active 
agent contained therein as the pH of the environment changes following 
administration to a patient in need of such prolonged payout. 
The percent of the ingredients required in the formulation of the 
invention, namely the active ingredient, the hydrophilic polymer, and the 
enteric polymer, is calculated on a dry weight basis without reference to 
any water or other components present. Thus, these three components 
together constitute 100 percent of the formulation for purposes of 
calculating individual percentages. If other ingredients are present, the 
sum of all of the components, with the exception of the filmcoating, if 
any, consitutes 100 percent of the formulation for purposes of calculating 
individual percentages. 
The active ingredient will be any compound which is suitable for oral 
administration, although this invention is particularly advantageous for 
weakly basic agents. The active agent will be present in a composition of 
the invention at a concentration in the range of about 0.1% by weight to 
about 90% by weight, more preferably at a concentration in the range of 
about 45% by weight to about 85% by weight. Typical medicaments which 
might benefit from this type of delivery system are exemplified by, but 
not limited to, the following classes of agents: beta-blockers such as 
propranolol, metoprolol, atenolol, labetolol, timolol and pindolol; 
antimicrobial agents such as cephalexin, cefaclor, cefadroxil, cefuroxime, 
cefuroxime axetil, erythromycin, penicillin, 
7-[D-(aminophenylacetyl)amino]-3-chloro-8- 
oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, also known as 
loracarbef, 
7-[amino[3-[(methylsulfonyl)amino]-phenyl]acetyl]amino]amino]-3-chloro-8-o 
xo-1-azabicyclo[4.2.0]- oct-2-ene-2-carboxylic acid, and 
7-[D-amino[3-[(ethylsulfonyl) 
amino]phenyl]acetyl]amino-3-chloro-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-ca 
rboxylic acid; antihypertensive agents such as clonidine, methyldopa and 
nifedipine; antihistamines such as chlorpheniramine and brompheniramine; 
tranquilizers such as diazepam, chlordiazepoxide and oxazepam; 
anticonvulsants; antinauseants; muscle relaxants; anti-inflammatory 
substances; psychotropics; antimanics; stimulants; decongestants; 
antianginal drugs; vasodilators; antiarrhythmics; vasoconstrictors; 
migraine treatments; antiemetics; diuretics; antispasmodics; 
antiasthmatics; anti-parkinson agents; expectorants; cough suppressants; 
mucolytics; vitamins; and mineral and nutritional additives. 
Examples of agents for which this invention is particularly suited are 
cephalexin and cefaclor. Both compounds are zwitterions, possessing both 
an acidic and a basic functional group. Both have greater solubility at 
the low pH values reported for gastric fluids (pH 1-3), than at the values 
normally reported for intestinal fluids (pH 5-7). When these compounds are 
placed into a conventional hydrogel, the release rate will be faster in 
simulated gastric fluids than when the formulation is exposed to simulated 
intestinal fluids. 
The compositions of the present invention will also contain a hydrophilic 
polymer. Hydrophilic polymers will be present in the compositions of the 
invention at a concentration in the range of about 5% by weight to about 
29% by weight, more preferably from about 5% by weight to about 20% by 
weight. Hydrophilic polymers suitable for use in this invention are either 
water soluble or water swellable, and include one or more natural or 
partially or totally synthetic anionic or nonionic hydrophilic gums, 
modified cellulosic substances stances or proteinaceous substances such as 
acacia, gum tragacanth, locust bean gum, guar gum, karaya gum, agar, 
pectin, carrageen, soluble and insoluble alginates, methylcellulose, 
hydroxypropyl methylcellulose, hydroxypropyl cellulose, 
hydroxyethylcellulose, sodium carboxymethylcellulose, 
carboxypolymethylene, gelatin, casein, zein, bentonite, magnesium aluminum 
silicate and the like. Other hydrophilic polymers which could be employed 
include polysaccharides and modified starch derivatives such as Amazio 
721A (American Maize Products) and Pullulan (Hayashibara Biochemical 
Laboratories, Inc.). 
Preferred hydrophilic polymers are the hydroxypropyl methylcelluloses 
manufactured by Dow Chemical and known as Methocel ethers. Preferred 
Methocel ethers include the Methocel E series gums (E 5, E 15, E 50, E4M, 
E10M and the like). The hydration rate of the Methocel E series gums is 
typically slower than the hydration rate of the Methocel K series gums. 
When the Methocel E series gums are used to prepare hydrogel tablets, 
thinner gel layers will result. As a consequence, when these tablets are 
exposed to a media of higher pH, the tablets respond more quickly than 
when polymers which provide thick viscous gel layers are employed. Yet 
another preferred polymer is Pullulan, a water soluble polysaccharide 
which is derived from starch. Pullulan is similar to the Methocel E series 
gums in that hydrogel tablets containing Pullulan normally form thin gel 
layers. When employed in conventional hydrogel tablets, Pullulan has only 
moderate ability to retard drug release. 
The formulations of the invention will also contain an enteric polymer. 
These polymers will be present in the compositions of the invention at a 
concentration in the range of about 0.5% by weight to about 25% by weight, 
more preferably at a concentration in the range of about 1.5% by weight to 
about 15% by weight. The pH at which these polymers begin to dissolve will 
be in the range of about 5.0 to about 7.4. The polymers will be insoluble 
at a pH below about 5.0. Since these polymers are insoluble at the low pH 
values corresponding to gastric fluids, they aid in retarding drug release 
in these regions. When exposed to fluids of higher pH, similar to those 
found in the small intestine, these polymers will dissolve, and thereby 
increase the permeability and rate of erosion of tablets of the present 
invention. Examples of suitable polymers include acrylic resins such as 
Eudragit L, Eudragit S, Eudragit L-100-55- Rohm Pharma, acrylic latex 
dispersions, for example, Eudragit L30D- Rohm Pharma, as well as other 
polymers such as cellulose acetate phthalate, polyvinyl acetate phthalate, 
and hydroxypropyl methylcellulose phthalate. A preferred enteric polymer 
is Eudragit L-100-55. This resin is available both as a fine powder or as 
an aqueous dispersion Eudragit L30D. This resin begins to dissolve above a 
pH of about 5.5, and for this reason aids in improving drug release over a 
major portion of the small intestine. The total concentration of the 
hydrophilic polymer and the enteric polymer will be less than 30% by 
weight of the total formulation. 
The present formulations may also contain a pharmaceutically acceptable 
binder at a concentration in the range of about 2.0% by weight to about 
10.0% by weight, preferably from about 2.0% by weight to about 6.0% by 
weight. Pharmaceutically acceptable binders suitable for use in the 
present formulations are chosen from those routinely used by formulation 
chemists and include sucrose, lactose, gelatin, starch paste, acacia, 
tragacanth, and other gums; cellulose derivatives such as methylcellulose, 
sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl 
methylcellulose, and ethylcellulose; microcrystalline cellulose; povidone; 
polyethylene glycols; corn syrup; and other binders known to those 
familiar with pharmaceutical formulations. Preferred binders are Pullulan 
and hydroxypropyl cellulose. 
The present formulations may also contain from about 2.0% to about 25.0% by 
weight of a pharmaceutically acceptable excipient, preferably from about 
5% to 20% by weight. These excipients may be water soluble and should be 
chemically inert to the other ingredients. Preferable excipients would 
include lactose and mannitol. Alternatively, a variety of other known 
excipients could be employed such as glucose, fructose, xylose, galactose, 
sucrose, maltose, xylitol, sorbitol, as well as other pharmaceutically 
acceptable monosaccharides and disaccharides. Other suitable excipients 
world include inorganic compounds such as the chloride, sulfate and 
phosphate salts of potassium, sodium, and magnesium, as well as the 
calcium and succinate salts of citrate, phosphate, lactate and gluconate. 
The present formulations may also contain a tablet lubricant. The lubricant 
will be present in the formulation at a concentration in the range of 
about 0.5% to about 4.0% by weight, preferably from about 1.0% to about 
2.5% by weight. Preferred lubricants are stearic acid, in powder form, and 
magnesium stearate. Other suitable tablet lubricants are calcium or zinc 
stearate, hydrogenated vegetable oils, talc, polyethylene glycols, mineral 
oil or other pharmaceutically acceptable die wall lubricants. 
If desired, other conventional tablet ingredients such as preservatives, 
stabilizers, glidants, pharmaceutically acceptable surface active agents, 
and FD&C colors may be included in the present formulations. The total 
weight of these ingredients is typically in the range of about 0.1% to 
about 2.0% of the weight of the formulation. Acceptable glidants or flow 
enhancers include colloidal silicon dioxide and talc. Acceptable surface 
active agents include sodium lauryl sulfate, dioctyl sodium sulfosuccinate 
(DSS), triethanolamine, polyoxyethylene sorbitan and poloxalkol 
derivatives, quaternary ammonium salts or other pharmaceutically 
acceptable surface active agents. Additionally, the lubricants and surface 
active agents can be combined and incorporated in the formulation as a 
single ingredient. 
The resulting tablets may be coated, if desired, with one of many readily 
available coating systems. Coating the tablets serves to mask the taste of 
the drug, make the tablet easier to swallow and, in some cases, improve 
the appearance of the dosage form. The tablets can be sugar coated 
according to procedures well known in the art, or can be coated with any 
one of numerous polymeric film coating agents frequently employed by 
formulation chemists. Representative examples of such film coating agents 
include hydroxypropyl methylcellulose, carboxymethylcellulose, 
hydroxypropyl cellulose, methylcellulose, ethylcellulose, acrylic resins, 
povidone, polyvinyl diethylaminoacetate, cellulose acetate phthalate, 
polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, 
acrylic latex emulsions, ethylcellulose latex emulsions or other 
commercially available preparations such as Pharmacoat, manufactured by 
Shin-Etsu Chemical Co., Ltd, and Opadry, manufactured by Colorcon, Inc. 
The present formulations may be prepared by procedures well known to 
formulation chemists. The method of manufacturing can affect the release 
characteristics of the finished tablets. The enteric polymer employed in 
the present formulations may be incorporated into the formulation in a 
number ways. The polymer may be added as a finely divided powder to the 
active agent along with all or part of the hydrophilic polymer. These 
ingredients are thoroughly mixed and granulated with either water or an 
aqueous solution of the hydrophilic polymer or other binder. This 
granulation is dried and sized. The resulting granulation may be blended 
with additional hydrophilic polymer and tablet lubricants, and then 
compressed into tablets. This particular method of manufacture requires a 
larger percentage of enteric polymer to yield the desired balance of 
appropriate release in both simulated gastric fluids and simulated 
intestinal fluids, but eliminates the need for organic solvents during the 
manufacture of the tablets. 
Alternatively, the enteric polymer can be added as a finely divided powder 
to the active agent and optionally all or part of the hydrophilic polymer. 
These ingredients are thoroughly mixed. Next, rather than using aqueous 
ingredients during the granulation step, organic solvents such as 
isopropyl alcohol, ethanol and the like may be employed with or without 
water. If desired, a suitable hydrophilic polymer can be dissolved in the 
solvent. Using this type of granulating fluid, the finely divided enteric 
polymer may become activated or partially dissolved during the granulation 
phase. In this state, it may be more effective in retarding drug release 
at low pH. This granulation is then processed as described above. This 
method of incorporation may result in reduced requirements for both the 
enteric polymer and hydrophilic polymer, which may be a significant 
advantage when the active agent is very soluble or is to be employed at 
high doses. 
A minor variation of the above method would be to dissolve the enteric 
polymer in an appropriate solvent system such as isopropyl alcohol, 
ethanol, and the like, with or without water. The resulting solution of 
the enteric polymer is then used to granulate the active agent which may 
optionally contain a portion of the hydrophilic polymer. This method of 
incorporation allows the enteric polymer to more effectively retard drug 
release at low pH. The resulting granulation is then processed as 
described above. This processing method may again result in reduced 
requirements for both the enteric polymer and hydrophilic polymer. 
A third method for incorporation of the enteric polymer into a composition 
of the invention requires using an aqueous latex dispersion of the polymer 
as the granulating fluid. In this instance, the active agent and all or 
part of the hydrophilic polymer would be thoroughly mixed. The dispersion 
of the enteric polymer is then added to complete the granulation. The 
resulting tablets have many of the properties of the solvent granulation 
tablets described above, but this method does not require the use of these 
solvents. The aqueous dispersion, however, may not possess much tackiness, 
and the hydrophilic polymer which may be required to yield a suitable 
granulation by this method, may yield tablets which do not have the 
desired release profile at high and low pH that can be achieved using 
other manufacturing procedures. 
The method of incorporation of the hydrophilic polymer will also have an 
effect on the release rate of the resulting tablets. These effects are 
well known to those familiar with hydrogel technology. It should be noted 
that when higher viscosity hydrophilic polymers are added to the 
formulation prior to wet granulation with aqueous solutions, the resulting 
tablets may have compromised release profiles when exposed to media of pH 
high enough to dissolve the enteric polymer. 
As noted above, examples of agents for which this invention is particularly 
suited are cephalexin and cefaclor. When these compounds were placed into 
a conventional hydrogel composition, the release rate was faster in 
simulated gastric fluids than when the formulation was exposed to 
simulated intestinal fluids. This characteristic is demonstrated by the 
following example: 
EXAMPLE A 
The following example is a cephalexin monohydrate sustained release tablet 
prepared using conventional hydrogel technology: 
______________________________________ 
Per Tablet Unit Formula 
weight (mg) 
______________________________________ 
cephalexin 1074.5 mg 
povidone-90 24.0 mg 
Methocel E4M Premium 161.3 mg 
stearic acid powder 15.1 mg 
magnesium stearate 15.1 mg 
______________________________________ 
The release tendencies of these tablets were evaluated using two 
dissolution procedures. One procedure is termed the "gastric method" and 
the other procedure is the "simulated GI method". According to the gastric 
method, the tablets were evaluated in 0.1 N hydrochloric acid which 
represents simulated gastric fluids. The simulated gastrointestinal (GI) 
method was designed to simulate gastrointestinal transit. According to the 
simulated GI method, the tablets were exposed for one hour to 750 ml of 
0.1 N hydrochloric acid, at which time the pH in the dissolution kettle 
was increased to pH 6.8 by the addition of 250 ml of 0.2 M tribasic sodium 
phosphate. The dissolution results of these tablets are presented below: 
______________________________________ 
Cephalexin Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 17 17 
60 28 28 
90 38 33 
120 48 34 
180 65 39 
240 79 44 
300 90 49 
360 98 55 
420 105 59 
______________________________________ 
The tablets were placed into a 10 mesh basket and were rotated in the 
above media at 100 rpm. 
The dissolution data illustrates a potential problem with the use of 
conventional hydrogel technology with a compound whose solubility declines 
as the pH is increased. With the above formulation, when the tablets were 
exposed to media of a higher pH in the simulated GI method, the release 
rate of cephalexin from the formulation declined dramatically. When used 
clinically, this formulation may not perform as intended if the dosage 
form does not remain in the stomach. Premature emptying of the tablet into 
the small intestine, and the resulting pH increase, could result in a 
decreased cephalexin release rate and poor bioavailability. These 
conditions would lead to potential problems if they occurred on a 
continued basis, such as therapeutic failure in the treatment of some 
types of infection. 
The following Examples illustrate the formulations of the invention, and 
methods of for their preparation. The Examples are not intended to be 
limiting to the scope of the invention in any respect and should not be so 
construed. 
EXAMPLE 1 
A Hobart mixer was charged with 2149 g of cephalexin monohydrate. The 
resulting mixture was granulated with 1000 ml of 15% w/v Eudragit L-100-55 
in a mixture of isopropyl alcohol:water (9:1, v:v). Total granulating time 
was between five to seven minutes. The wet granulation was placed through 
No. 4 screen onto paper-lined trays and dried at 35.degree. C. for five 
and one-half hours. Drying was continued at room temperature overnight. 
The dried granulation was placed through a No. 14 mesh screen into an 
appropriate container. 
A v-blender was charged with 575 g of this granulation and 62.5 g of 
hydroxypropyl methylcellulose E-50 to prepare 500 tablets. This mixture 
was blended for about thirty minutes. To the mixture was added stearic 
acid powder (7.5 g) and magnesium stearate (3.25 g) through a No. 30 mesh 
screen. This material was mixed for five minutes and discharged into an 
appropriate container. The resulting mixture was compressed on a Stokes 
F-press tabletting machine using conventional tooling. 
______________________________________ 
Per Tablet Unit Formula: 
weight weight 
(mg) (percent) 
______________________________________ 
cephalexin monohydrate 
1074.5 82.91 
Eudragit L-100-55 75.0 5.79 
hydroxypropyl methylcellulose E-50 
125.0 9.65 
stearic acid powder 15.0 1.15 
magnesium stearate 6.5 0.50 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods with the following results: 
______________________________________ 
Cephalexin Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 22 20 
60 35 32 
90 45 40 
120 53 50 
180 66 69 
240 77 84 
300 85 92 
360 94 93 
420 100 93 
______________________________________ 
EXAMPLE 2 
A Hobart mixer was charged with 1612 g of cephalexin monohydrate, 300 g of 
Eudragit L-100-55 and 225 g of hydroxypropyl methylcellulose E-5 through 
an appropriate screen. The mixture was blended thoroughly and granulated 
with 750 ml of an 8% w/v hydroxypropyl methylcellulose E-5 solution in a 
mixture of isopropyl alcohol and water (3:7, v:v). Total granulating time 
was between five and ten minutes. The wet granulation was placed through a 
No. 4 screen onto paper-lined trays and dried at 45.degree. C. for one 
half hour. Drying continued at room temperature for 48 hours. The dried 
granulation was placed through a No. 14 mesh screen into an appropriate 
container. 
A v-blender was charged with 732 g of this granulation followed by 11 g of 
stearic acid powder and 7.77 g of magnesium stearate were added through a 
No. 30 mesh screen. This material was mixed for five minutes and 
discharged into an appropriate container. The resulting mixture was 
compressed on a Stokes F-press tabletting machine using conventional 
tooling. 
The resulting tablets were film coated with a solvent based film coating 
mixture consisting of hydroxypropyl methylcellulose E-50 (1.581 weight 
percent) and glycerin (0.552 weight percent) in a conventional coating 
pan. The tablets were then placed onto paper-lined trays to dry to provide 
approximately 1000 tablets. 
______________________________________ 
Per Tablet Unit Formula: 
weight 
weight 
(mg) (percent) 
______________________________________ 
cephalexin monohydrate 
537.23 71.54 
Eudragit L-100-55 100.00 13.32 
hydroxypropyl methylcellulose E-5 
95.00 12.65 
stearic acid powder 11.00 1.46 
magnesium stearate 7.77 1.03 
clear film coat (theory) 
15.88 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods with the following results: 
______________________________________ 
Cephalexin Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 28 27 
60 48 46 
90 65 60 
120 82 73 
180 100 93 
240 100 99 
______________________________________ 
EXAMPLE 3 
A pony mixer was charged with 3224 g of cephalexin monohydrate, 300 g of 
Eudragit L-100-55 and 93 g of hydroxypropyl cellulose L.F. through an 
appropriate screen. The mixture was blended thoroughly and granulated with 
1200 ml of a 6% w/v aqueous hydroxypropyl cellulose L.F. solution. 
Purified water was added in a quantity sufficient to produce a 
satisfactory granulation. Total granulating time was between five and ten 
minutes. The wet granulation was placed through a No. 4 screen onto 
paper-lined trays and dried at 35.degree. C. for 201/2hours. The dried 
granulation was placed through a No. 12 mesh screen into an appropriate 
container. 
To prepare 1000 tablets, a v-blender was charged with 1230 g of this 
granulation, and 100 g Methocel E4M CR grade was added through a No. 30 
mesh screen. This mixture was blended for about 20 minutes, after which 15 
g stearic acid powder and 10.5 g magnesium stearate were added through a 
No. 30 mesh screen. This material was mixed for five minutes and 
discharged into an appropriate container. The resulting mixture was 
compressed on a Stokes F-press tabletting machine using conventional 
tooling. 
The resulting tablets were film coated with a solvent based film coating 
mixture consisting of hydroxypropyl methylcellulose E-50 (1.581 weight 
percent) and glycerin (0.552 weight percent) in a conventional coating 
pan. The tablets were placed onto paper-lined trays to dry. 
______________________________________ 
Per Tablet Unit Formula: 
weight weight 
(mg) (percent) 
______________________________________ 
cephalexin monohydrate 
1074.50 79.30 
Eudragit L-100-55 100.00 7.38 
hydroxypropyl cellulose L.F. 
55.00 4.06 
Methocel E4M CR grade 
100.00 7.38 
stearic acid powder 
15.00 1.11 
magnesium stearate 10.50 0.77 
clear film coat (theory) 
50.54 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods to provide the following results: 
______________________________________ 
Cephalexin Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 12 12 
60 31 30 
90 47 37 
120 60 41 
180 80 58 
240 93 72 
300 99 82 
360 103 89 
420 105 93 
______________________________________ 
EXAMPLE 4 
A Hobart mixer was charged with 1612 g of cephalexin monohydrate and 45 g 
of hydroxypropyl cellulose L.F. through an appropriate screen. This 
mixture was blended thoroughly and granulated with 500 ml of an aqueous 
dispersion Eudragit L30D (equivalent to 150 g Eudragit L-100-55). Purified 
water was added in a quantity sufficient to produce a satisfactory 
granulation. Total granulating time was between five and ten minutes. The 
wet granulation was placed through a No. 4 screen onto paper-lined trays 
and dried at 35.degree. C. for 20 hours. The dried granulation was placed 
through a No. 14 mesh screen into an appropriate container. 
To prepare 500 tablets, a v-blender was charged with 602 g of this 
granulation and 50 g of Methocel E4M CR grade was added through a No. 30 
mesh screen. This mixture was blended for about 20 minutes, after which 
7.5 g of stearic acid powder and 5.25 g magnesium stearate were added 
through a No. 30 mesh screen. This material was mixed for five minutes and 
discharged into an appropriate container. The resulting mixture was 
compressed on a Stokes F-press tabletting machine using conventional 
tooling. 
______________________________________ 
Per Tablet Unit Formula: 
weight weight 
(mg) (percent) 
______________________________________ 
cephalexin monohydrate 
1074.50 80.79 
Eudragit L30D (solids) 
100.00 7.52 
hydroxypropyl cellulose L.F. 
30.00 2.26 
Methocel E4M CR grade 
100.00 7.52 
stearic acid powder 
15.00 1.13 
magnesium stearate 10.50 0.78 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods to give the following results: 
______________________________________ 
Cephalexin Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 22 21 
60 33 32 
90 42 37 
120 50 39 
180 63 49 
240 75 67 
300 85 79 
360 93 85 
420 97 88 
______________________________________ 
EXAMPLE 5 
A Hobart mixer was charged with 2149 g of cephalexin monohydrate. This 
material was granulated with 1000 ml of a 10% w/v Eudragit L-100-55 in a 
mixture of isopropyl alcohol and water (9:1, v:v). Total granulating time 
was about seven minutes. The wet granulation was placed through a No. 4 
screen onto paper-lined trays and dried at 35.degree. C. for two hours. 
Drying was continued at room temperature overnight. The dried granulation 
was placed through a No. 14 mesh screen into an appropriate container. 
To prepare 300 tablets, a v-blender was charged with 337 g of the 
granulation and 45 g of hydroxypropyl methylcellulose E-50. This mixture 
was blended for about thirty minutes. Stearic acid powder (4.5 g) and 
magnesium stearate (1.95 g) were added to the mixture through a No. 30 
mesh screen. This material was mixed for five minutes and discharged into 
an appropriate container. The resulting mixture was compressed on a Stokes 
F-press tabletting machine using conventional tooling. 
______________________________________ 
Per Tablet Unit Formula: 
weight weight 
(mg) (percent) 
______________________________________ 
cephalexin monohydrate 
1074.5 82.91 
Eudragit L-100-55 50.0 3.86 
hydroxypropyl methylcellulose E-50 
150.0 11.57 
stearic acid powder 15.0 1.16 
magnesium stearate 6.5 0.50 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods with the following results: 
______________________________________ 
Cephalexin Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 24 24 
60 38 37 
90 47 46 
120 54 55 
180 73 76 
240 94 89 
300 99 94 
______________________________________ 
EXAMPLE 6 
A Hobart mixer was charged with 500 g of cefaclor monohydrate, 65 g of 
lactose and 100 g of hydroxypropyl methylcellulose E-5 through an 
appropriate screen. The mixture was blended thoroughly and granulated with 
350 ml of a 5% w/v Eudragit L-100-55 solution in a mixture of isopropyl 
alcohol and water (19:1, v:v). Total granulating time was between five and 
ten minutes. The wet granulation was placed through a No. 4 screen onto 
paper-lined trays and dried at 50.degree. C. for one hour. Drying 
continued at room temperature for 48 hours. The dried granulation was 
passed through a No. 16 mesh screen into an appropriate container. 
To prepare 500 tablets, a v-blender was charged with 268 g of the 
granulation, and 3.75 g of stearic acid powder and 2.5 g of magnesium 
stearate were added through a No. 30 mesh screen. The resulting mixture 
was mixed for five minutes and discharged into an appropriate container. 
The resulting mixture was compressed on a Stokes F-press tabletting 
machine using conventional tooling. 
______________________________________ 
Per Tablet Unit Formula: 
weight 
weight 
(mg) (percent) 
______________________________________ 
cefaclor monohydrate 392.30 71.60 
lactose 50.98 9.30 
Eudragit L-100-55 13.71 2.50 
hydroxypropyl methylcellulose E-5 
78.45 14.32 
stearic acid powder 7.50 1.37 
magnesium stearate 5.00 0.91 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods with the following 
______________________________________ 
Cefaclor Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Stimulated GI Method 
______________________________________ 
30 22 23 
60 33 32 
90 41 54 
120 47 97 
180 61 112 
240 75 
300 85 
360 92 
420 97 
______________________________________ 
EXAMPLE 7 
A Hobart mixer was charged with 500 g of cefaclor monohydrate, 40 g of 
Eudragit L-100-55, 50 g of lactose and 75 g of Pullulan PI-20 through an 
appropriate screen. The mixture was blended thoroughly and granulated with 
200 ml of a 5% w/v hydroxypropyl cellulose L.F. solution in a mixture of 
isopropyl alcohol and water (19:1, v:v). Total granulating time was 
between five and ten minutes. The wet granulation was placed through a No. 
4 screen onto paper-lined trays and then dried at 50.degree. C. for two 
hours. Drying continued at room temperature for 24 hours. The dried 
granulation was placed through a No. 14 mesh screen into an appropriate 
container. 
A v-blender was charged with 266 g of the granulation, and 3.75 g stearic 
acid powder and 2.5 g of magnesium stearate were added to the blender 
through a No. 30 mesh screen. This material was mixed for five minutes and 
discharged into an appropriate container. The resulting mixture was 
compressed on a Stokes F-press tabletting machine using conventional 
tooling to provide 500 tablets. 
______________________________________ 
Per Tablet Unit Formula: 
weight 
weight 
(mg) (percent) 
______________________________________ 
cefaclor monohydrate 
392.30 73.43 
lactose 39.23 7.34 
Eudragit L-100-55 31.36 5.87 
Pullulan PI-20 58.85 11.02 
stearic acid powder 
7.50 1.40 
magnesium stearate 5.00 0.94 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods to afford the following results: 
______________________________________ 
Cefaclor Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
______________________________________ 
30 18 
60 24 
90 30 
120 34 
180 44 
240 50 
300 56 
360 61 
420 66 
______________________________________ 
EXAMPLE 8 
A Hobart mixer was charged with 1177 g of cefaclor monohydrate, 212 g of 
mannitol and 176 g of hydroxypropyl methylcellulose E-5 through an 
appropriate screen. The mixture was blended thoroughly and granulated with 
720 ml of a 5% w/v Eudragit L-100-55 solution in a mixture of isopropyl 
alcohol and water (9:1, v:v). Total granulating time was five minutes. The 
wet granulation was placed through a No. 4 screen onto paper-lined trays 
and dried at 40.degree. C. for three hours. Drying continued at room 
temperature overnight. The dried granulation was placed through a No. 16 
mesh screen into an appropriate container. 
To prepare 1500 tablets, a v-blender was charged with 800 g of this 
granulation. Stearic acid powder (11.25 g) and magnesium stearate (7.5 g) 
were added to the blender through a No. 30 mesh screen. The resulting 
material was mixed for five minutes and discharged into an appropriate 
container. The resulting mixture was compressed on a Stokes F-press 
tabletting machine using conventional tooling. 
______________________________________ 
Per Tablet Unit Formula: 
mg/tablet 
% w/w 
______________________________________ 
cefaclor monohydrate 
392.30 71.83 
mannitol 70.70 12.95 
hydroxypropyl methylcellulose E-5 
58.50 10.71 
Eudragit L-100-55 12.00 2.20 
stearic acid powder 7.50 1.37 
magnesium stearate 5.00 0.94 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods with the following results: 
______________________________________ 
Cefaclor Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 20 21 
60 31 30 
90 38 61 
120 46 111 
180 63 
240 79 
300 91 
360 98 
420 103 
______________________________________ 
EXAMPLE 9 
A Hobart mixer was charged with 1177 g of cefaclor monohydrate, 212 g of 
mannitol and 176 g of hydroxypropyl methylcellulose E-5 through an 
appropriate screen. The mixture was blended thoroughly and then granulated 
with 720 ml of a 5% w/v Eudragit L-100-55 solution in a mixture of 
isopropyl alcohol and water (9:1, v:v). Total granulating time was about 
five minutes. The wet granulation was placed through a No. 4 screen onto 
paper-lined trays and dried at 40.degree. C. for three hours. Drying 
continued at room temperature overnight. The dried granulation was placed 
through a No. 16 mesh screen into an appropriate container. 
To prepare 1100 tablets, a v-blender was charged with 587 g of this 
granulation and 26.4 g of mannitol. This mixture was blended for about 
thirty minutes and combined with stearic acid powder (8.25 g) and 
magnesium stearate (5.5 g) through a No. 30 mesh screen. This material was 
mixed for five minutes and discharged into an appropriate container. The 
resulting mixture was compressed on a Stokes F-press tabletting machine 
using conventional tooling. The resulting tablets were film coated with a 
solvent based film coating mixture consisting of hydroxypropyl 
methylcellulose E-50 (1.55 weight percent), glycerin (0.54 weight percent) 
and Opaspray Blue (solids - 0.75 weight percent) in a conventional coating 
pan. The tablets were then placed onto paper-lined trays to dry. 
______________________________________ 
Per Tablet Unit Formula: 
weight 
weight 
(mg) (percent) 
______________________________________ 
cefaclor monohydrate 392.30 68.82 
mannitol 94.70 16.61 
hydroxypropyl methylcellulose E-5 
58.50 10.26 
Eudragit L-100-55 12.00 2.11 
stearic acid powder 7.50 1.32 
magnesium stearate 5.00 0.88 
color film coating (theory) 
13.01 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods with the following results: 
______________________________________ 
Cefaclor Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 18 18 
60 28 28 
90 36 53 
120 46 95 
180 66 
240 83 
300 93 
360 97 
______________________________________ 
EXAMPLE 10 
A Hobart mixer was charged with 1569 g o cefaclor monohydrate, 201 g of 
mannitol and 264 g of hydroxypropyl methylcellulose E-5 through an 
appropriate screen. The mixture was blended thoroughly and granulated with 
960 ml of a 5% w/v Eudragit L-100-55 solution in a mixture of isopropyl 
alcohol and water (9:1, v:v). Total granulating time was about six 
minutes. The wet granulation was placed through a No. 4 screen onto 
paper-lined trays and dried at 28.degree. C. for six hours. Drying 
continued at room temperature overnight. The dried granulation was passed 
through a No. 16 mesh screen into an appropriate container. 
To prepare 1500 tablets, a v-blender was charged with 781 g of the 
granulation, 11.25 g of stearic acid powder and 7.5 g of magnesium 
stearate. The lubricants were added through a No. 30 mesh screen. This 
material was mixed for five minutes and discharged into an appropriate 
container. The resulting mixture was then compressed on a Stokes F-press 
tabletting machine using conventional tooling. The resulting tablets were 
film coated with a solvent based film coating mixture consisting of 
hydroxypropyl methylcellulose E-50 (1.55 weight percent), glycerin (0.54 
weight percent) and Opaspray Blue (solids--0.75 weight percent) in a 
conventional coating pan. The tablets were then placed onto paper-lined 
trays to dry. 
______________________________________ 
Per Tablet Unit Formula: 
weight 
weight 
(mg) (percent) 
______________________________________ 
cefaclor monohydrate 392.30 73.60 
mannitol 50.20 9.42 
hydroxypropyl methylcellulose E-5 
66.00 12.38 
Eudragit L-100-55 12.00 2.25 
stearic acid powder 7.50 1.41 
magnesium stearate 5.00 0.94 
color film coating (theory) 
12.87 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods with the following results: 
______________________________________ 
Cefaclor Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 17 17 
60 26 26 
90 33 45 
120 38 82 
180 49 
240 58 
300 67 
360 76 
420 83 
______________________________________ 
EXAMPLE 11 
A Hobart mixer was charged with 1046 g of cefaclor monohydrate, 80 g of 
mannitol and 70 g of hydroxypropyl methylcellulose E-5 through an 
appropriate screen. The mixture was blended thoroughly and then granulated 
with 500 ml of a 3% w/v Eudragit L-100-55 w/v hydroxypropyl cellulose EF 
solution in a mixture of isopropyl alcohol and water (isopropyl alcohol 90 
parts : 10 parts water). Total granulating time was between three and four 
minutes. The wet granulation was placed through a No. 4 screen onto 
paper-lined trays and then dried at 40.degree. C. for five hours. Drying 
continued at room temperature for 24 hours. The dried granulation was 
placed through a No. 16 mesh screen and the granulation was returned to 
paper-lined trays and dried at 40.degree. C. for 21/2 hours to remove 
residual solvent. 
To prepare 900 tablets, a v-blender was charged with 550.8 g of this 
granulation. To this, 61.2 g of hydroxypropyl methylcellulose E-50 was 
added through a No. 30 mesh screen. The mixture was blended for twenty 
minutes in a v-blender. To this mixture, the lubricants stearic acid 
powder (6.3 g) and magnesium stearate (2.7 g) were added through a No. 30 
mesh screen. This material was mixed for five minutes and discharged into 
an appropriate container. The resulting mixture was then compressed on a 
Stokes F-press tableting machine using conventional tooling. 
The tablets were film coated with a solvent based film coating mixture 
consisting of hydroxypropyl methylcellulose E-50 (1.581 weight percent), 
glycerin 0.552 (weight percent) and Opaspray Blue (1.961 weight percent) 
in a conventional coating pan. The tablets were placed onto paper-lined 
trays to air dry. 
______________________________________ 
Per Tablet Unit Formula: 
weight weight 
(mg) (percent) 
______________________________________ 
cefaclor monohydrate 523.00 75.80 
mannitol 40.20 5.80 
hydroxypropyl methylcellulose E-5 
35.00 5.07 
Eudragit L-100-55 7.50 1.09 
hydroxypropyl cellulose EF 
6.50 0.94 
hydroxypropyl methylcellulose E-50 
68.00 9.86 
stearic acid powder 7.00 1.01 
magnesium stearate 3.00 0.43 
blue film coating (theory) 
12.50 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods with the following results: 
______________________________________ 
Cefaclor Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 16 17 
60 30 34 
90 44 56 
120 57 71 
180 81 88 
240 101 100 
______________________________________ 
EXAMPLE 12 
To prepare 40 tablets, the following ingredients were passed through a No. 
30 mesh screen and mixed together in a mortar and pestle- 8.44 g of 7- 
[D-(aminophenylacetyl)amino]-3-chloro-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2 
-carboxylic acid monohydrate, 0.84 g of Eudragit L-100-55, and 2.56 g of 
hydroxypropyl methylcellulose E-50. To this mixture, 0.104 g of magnesium 
stearate and 0.216 g of talc were added and blended thoroughly. The 
resulting mixture was then compressed on a Stokes F-press tableting 
machine using conventional tooling. 
______________________________________ 
Per Tablet Unit Formula: 
weight weight 
(mg) (percent) 
______________________________________ 
7-[D-(aminophenylacetyl)amino]- 
211.00 69.41 
3-chloro-8-oxo-1-azabicyclo- 
[4.2.0]oct-2-ene-2-carboxylic 
acid monohydrate 
Eudragit L-100-55 21.00 6.91 
hydroxypropyl methylcellulose E-50 
64.00 21.05 
magnesium stearate 2.60 0.86 
talc 5.40 1.78 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods with the following results: 
______________________________________ 
Active Agent Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 23 24 
60 43 44 
90 65 59 
120 80 68 
150 92 79 
180 100 87 
240 105 99 
300 104 105 
______________________________________ 
EXAMPLE 13 
To prepare 40 tablets, the following ingredients were passed through a No. 
30 mesh screen and mixed together in a mortar and pestle- 8.0 g of 
7-[[amino 
[3-[(methylsulfonyl)amino]phenyl]acetyl]amino]-3-chloro-8-oxo-1-azabicyclo 
[4.2.0]oct-2-ene-2-carboxylic acid, 0.8 g of Eudragit L-100-55, 1.6 g of 
hydroxypropyl methylcellulose E-50, and 0.96 g of Methocel E4M CR grade. 
To this mixture, 0.120 g of magnesium stearate and 0.200 g of talc were 
added and blended thoroughly. The resulting mixture was then compressed on 
a Stokes F-press tableting machine using conventional tooling. 
______________________________________ 
Per Tablet Unit Formula: 
weight weight 
(mg) (percent) 
______________________________________ 
7-[[amino-[3-[(methylsulfonyl)- 
200.00 68.49 
amino]phenyl]acetyl]amino]-3- 
chloro-8-oxo-1-azabicyclo[4.2.0]- 
oct-2-ene-2-carboxylic acid 
Eudragit L-100-55 20.00 6.85 
hydroxypropyl Methylcellulose E-50 
40.00 13.70 
Methocel E4M CR grade 24.00 8.22 
magnesium stearate 3.00 1.03 
talc 5.00 1.71 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods with the following results: 
______________________________________ 
Active Agent Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 19 18 
60 29 28 
90 40 36 
120 50 40 
150 58 43 
180 65 48 
240 78 58 
300 89 69 
360 97 78 
420 100 84 
______________________________________ 
EXAMPLE 14 
To prepare 40 tablets, the following ingredients were passed through a No. 
30 mesh screen and mixed together in a mortar and pestle- 8.0 g of 7- 
D-[amino[3-[(ethyl-sulfonyl)amino]phenyl]acetyl]amino]- 
-chloro-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 0.8 g of 
Eudragit L-100-55, 1.6 g of hydroxypropyl methylcellulose E-50, and 1.0 g 
of Methocel E4M CR grade. To this mixture, 0.20 g of magnesium stearate 
and 0.200 g of talc were added and blended thoroughly. The resulting 
mixture was then compressed on a Stokes F-press tableting machine using 
conventional tooling. 
______________________________________ 
Per Tablet Unit Formula: 
weight weight 
(mg) (percent) 
______________________________________ 
7-[D-[amino[3-[(ethylsulfonyl)- 
200.00 67.80 
amino]phenyl]acetyl]amino]-3- 
chloro-8-oxo-1-azabicyclo[4.2.0]- 
oct-2-ene-2-carboxylic acid 
Eudragit L-100-55 20.00 6.78 
hydroxypropyl methylcellulose E-50 
40.00 13.56 
Methocel E4M CR grade 25.00 8.47 
magnesium stearate 5.00 1.69 
talc 5.00 1.69 
______________________________________ 
The dissolution of these tablets was evaluated by the previously described 
methods with the following results: 
______________________________________ 
Active Agent Dissolved (Cumulative Percent) 
Time 
(minutes) Gastric Method 
Simulated GI Method 
______________________________________ 
30 18 17 
60 27 28 
90 34 35 
120 43 39 
150 50 42 
180 56 47 
240 67 56 
300 76 65 
360 86 75 
420 92 84 
______________________________________