The invention disclosed is erythromycin microencapsulated granules activity densities greater than about 0.300 g/ml. These granules are unusually small having diameters less than about 1000 microns. The granules are particularly useful in hand-held flowable material dispensers. A process for manufacturing such granules is also disclosed.

BACKGROUND OF THE INVENTION 
Over the past several years it has become obvious to health professionals 
and the pharmaceutical industry that optimal therapy with existing drugs 
has not been achieved with conventional dosage forms (i.e. tablets, 
capsules, injectables, suppositories) and dosing regimens. The term 
"optimal therapy" means the safest, most rapid, and most convenient 
amelioration of any particular disease state. Further, the "safety" of a 
dosage form or dosing regimen refers to the frequency and severity of side 
reactions. Improvement in therapy can then be defined as any change in the 
dosage form or regimen for an existing drug that: (1) reduces the 
frequency and severity of side reactions, (2) increases the rate at which 
cure or control is achieved, and (3) decreases the degree of disruption of 
normal patient activities. 
In response to this growing perception, a number of novel drug delivery 
systems have been developed and brought to market. Some good examples are 
the transdermal delivery devices such as Nitro-Dur.RTM. (Key 
Pharmaceuticals), Nitro-Disc.RTM. (Searle), Transderm Nitro.RTM. (Ciba), 
Clonidine-TSS.RTM. (Boehringer-Ingelheim) and Transderm-Scop.RTM. (Ciba). 
Other examples are Theo-Dur.RTM. tablets, a sustained release form of 
theophylline, Theo-Dur Sprinkle.RTM. (U S. Pat. No. 4,587,118) and 
Slo-Bid.RTM.. Theo-Dur Sprinkle.RTM. and Slo-Bid.RTM. are 
microencapsulated forms of slow release theophylline that are intended for 
use in pediatric patients or other patients who may have difficulty in 
swallowing a tablet. The microcapsules are supplied in hard gelatin 
capsules. The hard gelatin capsules are opened at the point of use by the 
care-giver and administered in a soft food. 
This form of drug delivery has significant drawbacks. First, there are a 
small finite number of capsule sizes marketed, and this limits the 
physician's ability to prescribe an appropriate dose on the basis of a 
particular patient's weight, severity of disease, and therapeutic 
response. Second, there is the possibility of tampering which has become a 
subject of major concern related to the safety of over-the-counter 
pharmaceutical products. 
Flowable material dispensers such as that described in U.S. Pat. No. 
4,579,256 were developed to overcome these drawbacks. The Flowable 
Material Dispenser is an adjustable, metering and dispensing package. The 
dispenser can accurately deliver a granular pharmaceutical product to a 
patient by pouring the selected dosage onto a small quantity of soft food 
contained on a spoon prior to swallowing. The dispenser is child- and 
tamper-resistant, protects the product from the surrounding environment 
and precisely delivers an adjustable dose well within the compendial 
requirements for uniformity of dosage units. However, microcapsules that 
are suitable for use in the Flowable Material Dispenser must meet certain 
narrow specifications with regard to average particle size, particle size 
distribution, shape, and active agent concentration. 
These specifications are generally defined as follows: 
______________________________________ 
Particle size/size distribution 
A: 710 Microns - 1000 
(depending on dispenser design) 
Microns 
B: 590 microns - 840 
microns 
C: 500 microns - 710 
microns 
Activity Density not less than 0.300 g/ml 
(potency .times. bulk density) 
Appearance nearly spherical 
Flow freely flowing 
______________________________________ 
Although an acceptable product could be made beyond the limits of these 
parameters, high potency and small size are required to achieve the 
necessary bulk density which insures that the largest dose is contained in 
a volume that is convenient to swallow. Small size is also essential if 
the particles are to be relatively impalpable when added to soft food. 
High bulk density allows a dispenser of reasonable size for one hand 
operation to contain a ten to sixty day supply of drug. Narrow size 
distribution insures reproducibility of each measured dose and eliminates 
variation in bulk density due to segregation of sizes. This is critical to 
a device which measures solid particles by volume. Narrow particle size 
distribution also implies reproducibility of bulk density from batch to 
batch. Thus, the same volume will contain the same amount of drug every 
time in production, which is a new requirement, imposed by the flowable 
material dispenser but not by prior art delivery systems such as hard 
gelatin capsules. It is also important that the microcapsules be nearly 
spherical to impart the flow characteristics that are required at every 
stage of assembly and use of the dispenser. The nearly spherical aspect of 
the microcapsules also enhances product elegance. 
Presently available conventional pharmaceutically active granules are 
generally inappropriate for oral administration with semi-solid food or 
for use in a hand-held flowable material dispenser. These conventional 
granules are large and create a noticeable gritty mouthfeel for the 
patient. Large microgranule size also necessitates an increase in the 
smallest characteristic dimension of the measuring cylinder and the flow 
channels of the flowable material dispenser if particle bridging is to be 
avoided. An increase in the smallest characteristic dimension of the 
measuring cylinder is also necessary if the requirements of the United 
States Pharmacopeia for Uniformity of Dosage Units are to be met. As those 
characteristic dimensions increase, so does the overall size of the 
flowable material dispenser. Each increase in size of the dispenser 
results in the loss of a degree of convenience in its use. At some 
microgranule size larger than 18 mesh (1000 microns), the flowable 
material dispenser becomes too large to be comfortably hand-held and 
hand-operated. 
Conventional granules are also difficult to accurately dispense from a 
hand-held flowable material dispenser due to the broad size distribution 
of granules both within and between batches, as well as the lack of 
uniform shape of the conventional granules. Erythromycin is uniquely 
suited for incorporation into a flowable material dispenser because of the 
complexity of its pharmacodynamic and pharmacokinetic profile. It is well 
known that dose-related gastrointestinal upsets (epigastric distress, 
nausea, vomiting and diarrhea) occur commonly with erythromycin 
administration. It is this adverse effect that the present invention is 
intended to eliminate. It is believed that much of the gastrointestinal 
distress that occurs during erythromycin therapy is due to overdose and 
that accurate delivery of the appropriate dose by weight will provide 
significant therapeutic advantages. 
SUMMARY OF THE INVENTION 
The present invention relates to pharmaceutically active microencapsulated 
granules comprising erythromycin and a binder which have an unexpectedly 
high concentration (average activity density greater than about 0.300 
g/ml), small size (less than about 1000 microns diameter), narrow size 
distribution, and uniformity of shape (spherical). A number of binders or 
combinations of binders may be used in the erythromycin granules, 
including hydroxypropyl methylcellulose phthalate, cellulose acetate 
phthalate, polyvinyl acetate phthalate, polyvinylpyrrolidone, 
hydroxypropyl methylcellulose, polyethylene glycol, hydroxypropyl 
cellulose and polyethylene oxide. However, a preferred binder is a mixture 
of polyethylene oxide and polyethylene glycol. 
The invention further relates to a preferred method of manufacturing the 
erythromycin granules using fluidized bed techniques to apply coatings to 
seeds. The use of fluidized bed techniques also aids in achieving the 
granule properties of high concentration, small size, narrow size 
distribution and uniform shape.

DETAILED DESCRIPTION OF THE INVENTION 
The invention relates to pharmaceutically active microencapsulated granules 
comprising erythromycin and a binder. Such erythromycin granules are 
particularly useful in flowable material dispensing devices. One such 
dispensing device is the "Flowable Material Dispenser" disclosed in U.S. 
Pat. No. 4,579,256 incorporated herein by reference. 
In order for pharmaceutically active granules to be used in the 
above-described dispenser, such granules must exhibit a high concentration 
of pharmaceutically active agent, a small size, a narrow size distribution 
and a uniformity of shape, preferably spherical. They must also be 
resilient enough to withstand packaging on high speed filling equipment 
and shipment throughout the world. The uniformly spherical granules ensure 
the accuracy and reproducibility of doses from the dispenser. The 
properties of high concentration and small size are necessary for 
convenience of administration by minimizing the amount of granules the 
patient has to swallow. The high concentration and small size, along with 
the narrow size distribution of uniformly spherical granules are also 
desirable so that the granules do not create an unpleasant gritty feeling 
in the patient's mouth when the granules are ingested with the food on 
which they are dispensed. Small average size is also necessary if the 
flowable material dispenser is to be kept small enough to be hand-held and 
hand-operated. 
The erythromycin granules which meet the above concentration, size and 
shape requirements comprise a starting seed which has an active coating 
applied thereto. The active coating comprises erythromycin and a binder. 
Erythromycin is a well-known antibiotic which is available as white or 
slightly yellow crystals or powder. It is slightly hygroscopic and has a 
pK.sub.a of 8.7. Erythromycin is very slightly soluble in water, and 
freely soluble in alcohol, chloroform, ether and acetone, and moderately 
soluble in amyl acetate and ethylene dichloride. 
Suitable binders for use with the erythromycin include hydroxypropyl 
methylcellulose phthalate, polyvinylpyrrolidone, hydroxypropyl 
methylcellulose, polyethylene glycol, hydroxylpropyl cellulose, 
polyethylene oxide, cellulose acetate phthalate, polyvinyl acetate 
phthalate and mixtures thereof. A preferred binder comprises a mixture of 
polyethylene oxide and polyethylene glycol. The use of the polyethylene 
oxide/polyethylene glycol binder aids in achieving the required granule 
properties of the high concentration, small size, narrow size 
distribution, uniform shape, resiliency, and rapid dissolution in basic 
media. 
Polyethylene oxide is a polymer resin having the formula: 
EQU (o--CH.sub.2 CH.sub.2).sub.n 
where n determines the degree of polymerization and may range from about 
2,000 to about 100,000 depending upon the viscosity grade of the resin. 
Each repeating unit shown above has a molecular weight of 44, and 
therefore the corresponding molecular weights of the resins range from 
about 100,000 to about 5 million. 
Preferred polyethylene oxide resins for use in microencapsulated granules 
have molecular weights ranging from about 100,000 to about 900,000, and 
viscosities of about 10 cps of 5% solution to about 16,000 cps of 5% 
solution at 25.degree. C. as measured by Brookfield.RTM. viscometer or 
suitable equivalent instrumentation. Preferred polyethylene oxide resins 
are supplied as a white powder with a melting point of 65.degree. C. 
(149.degree. F). Chemically, polyethylene oxide resins are polyethers, are 
nonionic, and are water soluble. Polyethylene oxide resins are supplied by 
Union Carbide under the trademark Polyox.RTM.. 
The other component of the binder, polyethylene glycol, is also a polymer 
resin and has the formula: 
EQU H(OCH.sub.2 CH.sub.2).sub.n OH 
where n is greater than or equal to 4, and generally ranges between 4 and 
about 210. Polyethylene glycol may be prepared by reacting ethylene glycol 
with ethylene oxide in the presence of sodium hydroxide (NaOH) at 
temperatures in the range of 120.degree. C. (248.degree. F.) to 
135.degree. C. (275.degree. F.) under a pressure of about 4 atmospheres. 
Depending on its molecular weight, polyethylene glycol may be a clear 
viscous liquid or a white waxy solid at room temperature. 
Polyethylene glycol with molecular weights between about 190 and about 900 
are viscous liquids, while those with molecular weights of about 1000 to 
about 9000 are waxy solids. The viscosity of polyethylene glycol is 
measured at 99.degree. C. (210.degree. F.) and ranges from about 4.3 
centistokes to about 900 centistokes. The freezing point of polyethylene 
glycol ranges from about 4.degree. C. (39.degree. F.) to about 63.degree. 
C. (145.degree. F.). As the molecular weight of polyethylene glycol 
increases its water solubility, vapor pressure, hygroscopicity, and 
solubility in organic solvents decreases. In contrast, the freezing or 
melting range, specific gravity, flash point and viscosity increases as 
its molecular weight increases. Preferred polyethylene glycols are those 
with molecular weights from about 1000 to about 9000. 
In the preferred binder, polyethylene oxide is present as about 52% by 
weight to about 72% by weight of the binder and polyethylene glycol is 
present as about 28% by weight to about 48% by weight of the binder. In a 
particularly preferred binder, polyethylene oxide of molecular weight 
100,000 is present as about 62% by weight of the binder and polyethylene 
glycol 8000 is present as about 38% by weight of the binder. 
In the active coating, the weight ratio of erythromycin to polyethylene 
oxide/polyethylene glycol binder is preferably between about 5 to 1 and 
about 15 to 1. It is believed that there is an interaction of weak long 
range forces such as complexation, hydrogen bonding or Van der Wahl's 
forces between the erythromycin and the polyethylene oxide/polyethylene 
glycol binder of the active coating. Such an interaction is theorized 
based on a very slow dissolution rate for active seeds comprising 92% by 
weight erythromycin and 8% by weight polyethylene oxide, in simulated 
intestinal fluid ("SIF"). Both erythromycin alone and polyethylene oxide 
alone are very soluble in SIF. 
Additional evidence of a reaction between erythromycin and the polyethylene 
oxide/polyethylene glycol binder is found in the fact that the dissolution 
of an active seed comprising 95% by weight erythromycin and 5% by weight 
polyethylene oxide increases while the resilience of the seed decreases. 
Further, when a combination of polyethylene oxide and polyethylene glycol 
is used as the binder at the 8% level by weight, the dissolution remains 
rapid but the seeds are not as resilient as with 8% polyethylene oxide 
alone. This data also implies that the interaction between erythromycin 
and polyethylene glycol is not as strong as that between erythromycin and 
polyethylene oxide. Finally, when additional amounts of polyethylene oxide 
and polyethylene glycol are used as a protective coating, (i.e., intimate 
contact between molecules of erythromycin and molecules of these 
substances is avoided) the dissolution is also rapid and resilience 
increases. The data pertaining to this postulated interaction is presented 
in Example 14. It can also be seen in Example 10 that the presence of 
ethyl acetate increased the resilience of seeds manufactured with 
hydroxypropylmethylcellulose phthalate as the binder. However, that 
resilience was lost when the ethyl acetate was removed from the process. 
This indicates that a similar interaction occurs between erythromycin and 
ethyl acetate. 
When applied to the starting seed, the active coating is applied as an 
active coating composition comprising erythromycin, a binder and a 
solvent. The coating composition is in the form of a solution or a 
suspension. 
Examples of suitable solvents for use in the coating composition include 
water, ethanol, methanol, isopropanol, acetone, methylene chloride, 
chloroform, ethyl acetate, carbon tetrachloride, benzene, methyl ethyl 
ketone and combinations thereof. Any number of these solvents may be 
combined to achieve the proper balance between solubility of binder and 
erythromycin, while still maintaining a pumpable and sprayable viscosity. 
Such a desired viscosity is between about 5 cps and about 100 cps as 
measured by Brookfield.RTM. viscometer or suitable equivalent 
instrumentation. Although the polyethylene oxide/polyethylene glycol 
binder is preferably dissolved in the solvent, the pharmaceutically active 
agent may be either dissolved or suspended in the solvent. 
The preferred solvent is a mixture of about 70-90% by weight methanol and 
about 10-30% by weight purified water. A particularly preferred solvent is 
a mixture of 80% by weight methanol and 20% by weight purified water. The 
preferred solution or suspension of erythromycin, binder and solvent, 
contains about 15-40% by weight erythromycin, about 1%-4% by weight 
polyethylene oxide/polyethylene glycol binder, and the remainder solvent. 
A particularly preferred solution or suspension contains about 23% by 
weight to 25% by weight erythromycin and about 2% by weight binder. As 
high an amount of solids as is possible in the solution or suspension is 
preferred in order to reduce the process time for manufacture of the 
granules. 
When preparing the active coating composition, the solvent mixture of 
methanol and water is first mixed. The binder is then added to the solvent 
mixture and then the erythromycin is blended in to complete the 
composition. 
Commonly used inert starting seeds on which the active coating composition 
is applied include nonpareil seeds, sucrose crystals, silica gel and ion 
exchange resins. The preferred size range for inert starting seeds is 
inversely related to the average daily dose of the drug in question. In 
the case of high dose drugs like erythromycin, it is desirable to start 
with the smallest seed possible to obtain the greatest finished drug 
content. This minimizes the total volume of microcapsules that must be 
ingested. However, the difficulty encountered in coating discrete seeds 
smaller than 175 microns increases dramatically. A 60/80 mesh (177 
microns-250 microns) starting seed represents the smallest size that can 
be dealt with without using extraordinary measures. If drug crystals or 
granulation are to be used as the starting material rather than an inert 
seed, the preferred starting size would be between 25 and 40 mesh (approx. 
420-700 microns). The larger seed size serves to reduce the time required 
to apply additional drug to the seeds to meet the finished product seed 
size requirements of diameters less than 1000 microns. Usually, drug 
crystals or granulation of large size and suitable physical strength are 
not available on the open market for use as starting materials. Therefore, 
inert starting seeds are most commonly used in the present invention. 
The size of the finished granule is less than about 18 mesh (less than 
about 1000 microns diameter) and a preferred size is between about 18 mesh 
and about 25 mesh (about 710 microns to about 1000 microns diameter). The 
preferred starting seeds for the erythromycin microgranules are (60/80) 
sucrose crystals. The 25/30 nonpareil seeds are usually used with drugs 
which require lower daily doses, and the 60/80 sucrose crystals are 
usually used with drugs which require a higher daily dose. 
In one embodiment, the active coating composition is applied to the 
starting seed by use of a rotor granulator. Examples of conventional rotor 
granulators are the Vector Freund Spir-A-Flow.RTM. (one embodiment 
described in U.S. Pat. No. 3,711,319) and the Glatt rotor granulator. In 
general, a rotor granulator comprises a processing chamber with a rotor at 
its lower portion. Air is introduced at the level of the rotor for 
fluidization of the product bed. This air may enter the chamber through 
the opening between the rotor and the stator and/or through a second 
opening about midway across the radius of the rotor. This introduction of 
air results in a spiral and twisting air pattern within the chamber. When 
the inert starting seeds are introduced into the chamber, the combination 
of rotor and air circulation pattern is purported to provide higher 
individual particle densities, and rounder and smoother seeds than 
conventional fluid-bed systems such as Wurster columns and conventional 
Glatt fluidized beds. 
Once the starting seeds have been fluidized in the rotor granulator, the 
solution or suspension of binder and erythromycin is introduced through 
spray guns mounted in the periphery of the stator near the bottom of the 
product chamber or near the top of the product chamber to spray on the 
product from above. Although the starting seeds could also be coated using 
conventional fluidized beds, the rotor granulator is purported to produce 
a more evenly coated product with a higher concentration of active agent 
and a greater uniformity of spherical shape of each coated seed. 
In addition to the purported benefit derived from use of the rotor 
granulator, the polyethylene oxide/polyethylene glycol binder also 
contributes to the unexpectedly high concentration of erythromycin in each 
coated seed. The high concentration of erythromycin in the coated seeds is 
not achievable with conventional binders even when such coated seeds are 
manufactured with a rotor granulator. 
Despite the purported benefits of the rotor granulator, it has been found 
that conventional fluidized bed techniques produce erythromycin 
microencapsulated granules which meet all of the requirements for use in a 
hand-held flowable material dispenser. Such fluidized bed techniques are 
well known to those skilled in the pharmaceutical manufacturing art. With 
regard to the present invention, fluidized bed techniques are the 
preferred method of manufacture for erythromycin microencapsulated 
granules. 
After the pharmaceutically active seed has been produced, a protective 
coating is preferably applied to it. The protective coating is preferably 
applied to the active seed by using a rotor granulator, although other 
conventional fluidized beds may be used instead of the rotor granulator. 
Following application of the protective coating, alternate applications of 
the active coating and the protective coating may optionally be applied to 
the coated seed until the desired concentration of erythromycin is present 
in the microencapsulated granule. 
A suitable protective coating comprises a mixture of about 52% by weight to 
about 72% by weight polyethylene oxide and about 28% by weight to about 
48% by weight polyethylene glycol. A preferred protective coating 
comprises a mixture of about 62% by weight polyethylene oxide and about 
38% by weight polyethylene glycol. 
The preferred polyethylene oxide is one with a molecular weight of about 
100,000 to about 900,000 and the preferred polyethylene glycol has a 
molecular weight between about 1000 and about 9000. The mixture is 
produced in the same manner and under the same conditions as the binder 
described above, and is dissolved in a suitable solvent such as those 
described above to produce a protective coating composition. 
A preferred protective coating composition contains about 10% by weight of 
the polyethylene oxide/polyethylene glycol mixture and about 90% water as 
the solvent. Water is the preferred solvent because erythromycin is not 
highly soluble in water and therefore there is little tendency for the 
active coating to dissolve or interact with the protective coating 
composition. The interaction of the erythromycin and the components of the 
protective coating when brought into intimate contact (as in the active 
coating composition), was seen to unacceptably slow the dissolution of the 
finished product in basic media. This protective coating composition also 
resulted in the strongest granules (i.e. was able to withstand extended 
processing times). 
Another advantage of the protective coating is that it permits the use of 
acetone as a solvent in an enteric coating composition which is applied to 
the active seed after a desired concentration of erythromycin has been 
achieved. Acetone and erythromycin have an undesired reaction which 
inhibits the removal of acetone from the finished product. The protective 
coating prevents this reaction. The prevention of this reaction is 
important because acetone is a preferred solvent for the enteric coating 
composition, and high levels of residual acetone in the finished product 
are deemed unacceptable toxicologically and with regard to stability. 
The desired concentration of pharmaceutically active agent in each 
microencapsulated granule is dependent on the nature of a course of 
therapy (dosage level and duration) for a particular drug, the storage 
capacity of the device that will be used to dispense the granules and the 
number of microcapsules that can be conveniently delivered to a spoonful 
of semisolid food and swallowed. In the case of erythromycin, it is 
desired that the microencapsulated granules have as high a concentration 
as possible. 
In a preferred embodiment, the erythromycin micro-encapsulated granules are 
dispensed from a device such as that described in U.S. Pat. No. 4,579,256. 
Micro-encapsulated granules of erythromycin used in these dispensers 
should have an activity density greater than about 0.300 g/ml and 
preferably about 0.420 g/ml to about 0.470 g/ml. Activity density is 
defined as the mass activity of active agent per unit of volume and is 
equal to the bulk density of the finished product (pharmaceutically active 
microencapsulated granule) in g/ml multiplied by the potency of the 
finished product in g/g. In order to achieve the preferred activity 
density, it is necessary to produce a microencapsulated granule of as high 
a potency and bulk density as possible. 
Since erythromycin has better absorption characteristics in the small 
intestine than in the stomach, an enteric coating is preferably applied to 
the erythromycin microencapsulated granules. Such differing absorptive 
characteristics are thought to be dependent on the comparative acidity of 
the stomach and the small intestine. The stomach is more acidic (pH of 
about 1.0) than the small intestine (pH of about 7.0). Erythromycin is not 
stable in an acidic environment. 
An enteric coating may also be applied to granules containing 
pharmaceutically active agents which are more irritating to the mucosa of 
the stomach than to the intestinal mucosa. Examples of pharmaceutically 
active agents with this characteristic are well known to those of ordinary 
skill in the art and include aspirin and divalproex sodium. Suitable 
enteric coatings may comprise cellulose acetate phthalate, polyvinyl 
acetate phthalate, acrylic resins such as Eudragit L.RTM., shellac, 
cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate or 
combinations thereof. 
A particularly useful enteric coating for application to the 
microencapsulated granules comprises between 3% (w/w) and 10% (w/w) 
hydroxypropyl methylcellulose phthalate. The enteric coating is applied as 
a enteric coating composition comprising a dispersion of hydroxypropyl 
methylcellulose phthalate in a solvent comprising either acetone alone or 
a combination of acetone and methanol. When a solvent combination of 
acetone and methanol is used, the preferred combinations comprise either 
about 75% (w/w) acetone and about 25% (w/w) methanol or about 50% (w/w) 
acetone and about 50% (w/w) methanol. Based on superior dissolution rates 
and taste-masking properties, a most preferred enteric coating comprises 
about 6% (w/w) hydroxypropyl methylcellulose phthalate applied in an 
enteric coating composition comprising a solvent mixture of about 75% 
(w/w) acetone and about 25% (w/w) methanol. It has been found that this 
particular ratio of the two solvents produces a finished product of 
greater stability. 
Another suitable enteric coating composition comprises about 5% (w/w) to 
about 10% (w/w) hydroxypropyl methylcellulose phthalate and a solvent 
comprising about 75% (w/w) methylene chloride and about 25% (w/w) 
methanol. The enteric coating applied by this composition is preferably 
present as about 3% (w/w) to about 10% (w/w) of the microencapsulated 
granule. 
As with the other coating compositions, the enteric coating composition is 
preferably applied using a fluidized bed technique. Following the enteric 
coating application, the microencapsulated granules may be subjected to a 
drying step. The microencapsulated granules are dried in the rotor 
granulator or fluidized bed processor at a temperature between about 
55.degree. C. (131.degree. F.) and about 80.degree. C. (176.degree. F.). 
Although the drying step reduces the residual solvent levels to a safe and 
acceptable level, lower residual solvent levels can be reached by 
performing an optional second drying step. The optional drying step is 
performed under a vacuum of 30 mm Hg at about 70.degree. C. (158.degree. 
F.) for about 23 hours and results in undetectable residual solvent levels 
in the microencapsulated granules. 
An additional optional step after the microencapsulated granules have been 
dried is the addition of an antistatic agent. About 0.75% by weight (based 
on the final product weight) of a suitable antistatic agent is added in 
the fluidized bed or rotor granulator after the final drying step. The 
fluidized bed is run for about five minutes to distribute the antistatic 
agent onto the micro-encapsulated granules. This amount of antistatic 
agent is sufficient to coat the granules and prevent the granules from 
sticking to the sides of the flowable material dispenser. The prevention 
of adherence between the granules and the dispenser serves to reduce 
variability in dosing which is more common when an antistatic agent is not 
used. 
Suitable antistatic agents include silicon dioxide, polacrilin, talc, 
magnesium stearate, calcium stearate, stearic acid and combinations 
thereof. The preferred antistatic agent is silicon dioxide. Silicon 
dioxide, unlike many of the other suitable antistatic agents, serves the 
dual purpose of being a moisture scavenger. The elimination of the excess 
moisture which usually develops from condensation due to climatic changes 
during shipping and storing, also aids in eliminating variable dosing 
problems and flow problems with the granules. 
The finished erythromycin microgranules may be used in a variety of dosage 
delivery system, including tablets, capsules and flowable material 
dispensers. When used in a tablet delivery system, the erythromycin 
microgranules are compressed or formed into a tablet using conventional 
pharmaceutical tabletting techniques. When used in a capsule delivery 
system, the erythromycin microgranules are used to fill water soluble 
capsules using conventional pharmaceutical capsule manufacturing 
techniques. When used in a flowable material dispenser delivery system, 
the erythromycin microgranules are used to fill the flowable material 
dispenser. 
The features and advantages of the invention are further demonstrated by 
the following examples. In this specification and in the following 
examples, all parts and percentages are by weight and all temperatures are 
in degrees centigrade unless expressly stated to be otherwise. 
EXAMPLE 1 
Preparation of Microencapsulated Erythromycin Granules 
A solution of 50.0 grams polyethylene oxide NF and 30.0 grams polyethylene 
glycol 8000 NF in a mixture of 2400 grams Methyl Alcohol NF and 600 grams 
Purified Water USP was prepared. The polyethylene oxide/polyethylene 
glycol 8000 solution was then mixed with 925 grams of Erythromycin 
Dihydrate USP for seven minutes until a translucent solution ("active 
coating composition") was formed. Another solution was made from 19.1 
grams Polyethylene Oxide NF and 11.5 grams Polyethylene Glycol 8000 NF in 
275.4 grams Purified Water USP ("protective coating composition"). 
The active coating composition was applied (sprayed) onto 500 grams of 
Sucrose NF (starting seeds) to form active seeds. The starting seeds were 
60/80 mesh size. The application of the coating took place after the 
sucrose had been fluidized in a Vector Freund Spir-A-Flow.RTM. rotor 
granulator. Once all the active coating composition had been sprayed onto 
the sucrose, the pump tubing was disconnected and rinsed with Methyl 
Alcohol NF. 
After the pump tubing was reconnected, the protective coating composition 
of polyethylene oxide and polyethylene glycol 8000 in water was applied 
(sprayed) onto the active seeds which had been fluidized in the rotor 
granulator. Once all of the protective coating composition had been 
applied to the seeds, the product was dried in the rotor granulator at 
55.degree. C. (131.degree. F.) for 15 minutes. The product was discharged 
into a suitable container and labelled Erythromycin Active I Seeds. 
A portion (500 grams) of the Active I Seeds were returned to the 
Spir-A-Flow.RTM.. A second active coating composition was prepared as 
described above and applied (sprayed) onto the Active I Seeds. After the 
tubing was rinsed with methanol as described above, a protective coating 
composition prepared as described above was then applied (sprayed) onto 
the seeds. The product was dried as described above, discharged into a 
suitable container and labelled Active II Seeds. 
A portion (614 grams) of the Active II seeds were returned to the 
Spir-a-flow.RTM.. A third active coating composition was prepared using 
49.3 grams of Polyethylene Oxide NF, and 29.6 grams of Polyethylene Glycol 
8000 NF in a mixture of 236.7 grams of Methyl Alcohol NF and 592 grams of 
Purified Water USP. The polyethylene oxide/polyethylene glycol 8000 
solution was then mixed with 907.5 grams of Erythromycin Dihydrate, USP, 
for 7 minutes until an active coating composition was formed. The active 
coating composition was applied to the Active II seeds, after which the 
tubing was rinsed (sprayed) with methanol. A third protective coating 
composition which had been prepared with 19.1 grams of Polyethylene Oxide 
NF and 11.5 grams of Polyethylene Glycol 8000 NF and 275.4 grams of 
Purified Water USP was applied to the seeds. The seeds were dried at about 
55.degree. C. (131.degree. F.) for 15 minutes. The seeds were discharged 
from the column and labelled Active III seeds. The tubing for the rotor 
granulator was again rinsed with methanol. 
An enteric coating composition was then prepared by mixing 76.6 grams 
Hydroxypropyl Methylcellulose Phthalate 20073 NF into a mixture of 1091 
grams Acetone NF and 364 grams Methyl Alcohol NF. A portion (1200 grams) 
of the Active III Seed were then fluidized in the rotor granulator, and 
the enteric coating composition applied by spraying the seeds. When all of 
the enteric coating composition had been applied, the seeds were dried in 
the rotor granulator at about 70.degree. C. (158.degree. F.) until a 
constant product temperature was obtained (58.degree. C., 136.degree. F.) 
after about 45 minutes. 
Finally, 9.6 grams of silicon dioxide NF was added to the dried fluidized 
granules in the rotor granulator. The rotor granulator was run for about 
five minutes, after which time the granules were uniformly coated with the 
silicon dioxide. 
The resulting erythromycin dihydrate microencapsulated granules had an 
activity density of 0.456 g/ml and were of uniform small size and uniform 
spherical shape. About 90% of the final granules were between 700 microns 
and 1000 microns in diameter. 
Table 1 below, shows the amounts of each ingredient in the final product. 
TABLE 1 
______________________________________ 
Qty. per 250 mg dose Qty. per Kg 
of Erythromycin Batch size 
base (mg) Ingredient (g) 
______________________________________ 
271* Erythromycin 799 
Dihydrate USP 
20.3 Hydroxypropyl Methyl- 
59.6 
cellulose Phthalate 
200731 NF 
20.7 Polyethylene Oxide 
60.8 
NF (MW 10,000) 
12.4 Polyethylene Glycol 
36.5 
8000 NF 
12.4 Sucrose NF 36.6 
2.6 Silicon Dioxide NF 
7.5 
805** Methanol NF 2370 
288** Acetone NF 849 
262** Purified Water USP 
771 
______________________________________ 
*Based on theoretical activity of 92%. The actual weight of erythromycin 
dihydrate used is calculated on a lot to lot basis according to the 
following formula: 
Actual amount of erythromycin dihydrate to charge 
=- 
##STR1## 
**Removed during processing 
EXAMPLE 2 
Reproducibility Study 
Using the process described in Example 1, above, three batches of final 
product were manufactured. A 24-fold buildup of the starting seeds was 
used to produce the final product for each batch. 
The final theoretical potency for each batch was approximately 730 mg/g. 
The final product of each batch was tested for potency and bulk density, 
and the results are set forth below in Table 2. 
TABLE 2 
______________________________________ 
Theore- 
tical Actual 
Activ- Activ- 
Theore- ity ity 
Bulk tical Actual Densi- Densi- 
Density Potency Potency 
ty ty 
Batch (G/ML) (G/G) (G/G) (G/ML) (G/ML) 
______________________________________ 
871103C 
.638 .728 .737 .464 .470 
871116A 
.625 .730 .738 .456 .461 
871117B 
.640 .732 .726 .468 .468 
______________________________________ 
The bulk densities, actual potencies and actual activity densities show a 
consistently reproducible final product. The average actual activity 
density for the three batches was 0.465 g/ml which was acceptable. This 
average value represents the average bulk density of the three batches 
multiplied by the average actual potency of the three batches. 
EXAMPLE 3 
Effect of Acetone/Methanol Ratio in the Enteric Coating Composition on the 
Dissolution Profile and Taste Mask Characteristics of the Final Product 
Three batches of erythromycin microencapsulated granules were manufactured 
following the procedure set forth in Example 1 above. However, the enteric 
coating composition of each batch was varied by the amount of acetone 
present in the solvent. Batch 871105A had an enteric coating composition 
solvent of 100% by weight acetone, Batch 871103C had an enteric coating 
composition solvent mixture of 75% by weight acetone and 25% by weight 
methanol, and Batch 871109A had an enteric coating composition solvent of 
50% by weight acetone and 50% by weight methanol. 
The dissolution of the final product of each batch was tested as well as 
the taste. The results of the test are set forth below in Table 3. 
TABLE 3 
______________________________________ 
Time 
Batch % Ct. Wt. (min) % Dissolved 
Comments 
______________________________________ 
871105A 
6 90 *70.7 Bitter taste 
120 *85.5 Acetone (100%) 
871103C 
6 90 79.3 No taste 
120 95.6 Ace/Meth (75/25) 
871109A 
6 90 *76.3 Slightly bitter 
120 *87.8 Ace/Meth (50/50) 
______________________________________ 
Dissolution testing for enteric coated pellets was performed as follows: 
90 minutes = 60 minutes in simulated gastric fluid ("SGF") and 30 minutes 
in simulated intestinal fluid ("SIF"). 
120 minutes = 60 minutes in SGF and 60 minutes in SIF. 
*Dissolution data based on theoretical potency. All other results based o 
measured potency. 
The erythromycin microencapsulated granules with an enteric coating 
composition solvent comprising a mixture of 75% by weight acetone and 25% 
by weight methanol (Batch 871103C) not only had the best dissolution 
characteristics, but also had the best taste mask characteristics. 
EXAMPLE 4 
Stability of Erythromycin Microencapsulated Granules 
Three batches of erythromycin microencapsulated granules were prepared in 
accordance with Example 1 (Batches 871103C-1, 871116A-1 and 871109A-1). 
Batches 871103C-1 and 871116A-1 were prepared with an enteric coating 
composition solvent comprising 75% by weight acetone and 25% by weight 
methyl alcohol. However, Batch 871109A-1 was prepared with a mixture 
comprising 50% by weight acetone and 50% by weight methyl alcohol as the 
enteric coating composition solvent. 
After manufacture, finished microgranules of each batch were sealed in 
prototype hiMedics, Inc.'s Flowable Material Dispensers (U.S. Pat. No. 
4,579,256). Stability data was determined following storage at room 
temperature and at elevated temperature and humidity. The stability data 
for each batch (871103C-1, 871116A-1 and 871109A-1) is presented below in 
Tables 4A, 4B and 4C, respectively. 
TABLE 4A 
__________________________________________________________________________ 
Batch: #871103C-1 Batch Size (KG): 1.3 Theoretical Potency (mg/g): 
__________________________________________________________________________ 
723.0 
Parameter Initial 
3 M RT 
6 M RT 
Specifications 
__________________________________________________________________________ 
Potency (mg/g) 726.0 
823.0 
769.0 
658.0-840.0 act/gr 
Potency (% Theory) 
99.7 
113.0 
105.6 
Potency (% of Initial) 
100.0 
113.4 
105.9 
90.0-115.0% LC 
Loss of Dryness (% loss) 
0.35 
0.64 0.93 Report Value 
Water (%) 3.52 
2.10 2.96 Report Value 
Appearance Pass 
Pass Pass Free Flowing White to Off-white 
Uniform Spheres 
Odor None 
None None Report Odor 
Taste Pass 
Pass Pass None to Slight Bitter 
Bulk Density (g/ml) 
0.638 
0.645 
0.615 
Report Value 
Dissolution Fluid: 
92.1 
92.8 92.6 NLT 80% @ 120 min 
Acid & SIF @ 50 rpm 
Interval 120 mins (% Release) 
__________________________________________________________________________ 
Parameter Initial 
1 M 37/75 
2 M 37/75 
3 M 37/75 
6 M 37/75 
Specifications 
__________________________________________________________________________ 
Potency (mg/g) 
726.0 
739.0 784.0 796.0 759.0 658.0-840.0 act/gr 
Potency (% Theory) 
99.7 
105.5 107.7 109.3 104.3 
Potency (% of Initial) 
100.0 
101.8 108.0 109.6 104.5 90.0-115.0% LC 
Loss of Dryness (% loss) 
0.35 
1.96 2.24 1.80 2.73 Report Value 
Water (%) 3.52 
3.87 6.14 3.75 4.52 Report Value 
Appearance Pass 
Pass Pass Pass Pass Free Flowing White to 
Off-white 
Uniform Spheres 
Odor None 
None None None None Report Odor 
Taste Pass 
Pass Pass Pass Pass None to Slight Bitter 
Bulk Density (g/ml) 
0.638 
0.641 0.661 0.653 0.627 Report Value 
Dissolution Fluid: 
92.1 
91.1 95.7 86.2 77.6 NLT 80% @ 120 min 
Acid & SIF @ 50 rpm 
Interval 120 mins 
(% Release) 
__________________________________________________________________________ 
Storage Conditions: 
RT = Room Temperature 15-30.degree. C. 
37/75 = 35-40.degree. C. with 70-80% Relative Humidity 
M = Month 
TABLE 4B 
__________________________________________________________________________ 
Batch: #871116A-1 Batch Size (KG): 1.0 Theoretical Potency (mg/g): 
730.00 
__________________________________________________________________________ 
Parameter Initial 
3 M RT 
6 M RT 
Specifications 
__________________________________________________________________________ 
Potency (mg/g) 
761.0 
733.0 
752.0 
658.0-840.0 act/gr 
Potency (% Theory) 
104.2 
105.8 
103.0 
Potency (% of Initial) 
100.0 
105.4 
98.8 90.0-115.0% LC 
Loss of Dryness (% loss) 
0.05 
0.35 0.50 Report Value 
Water (%) 2.91 
2.62 3.36 Report Value 
Appearance Pass 
Pass Pass Free Flowing White 
to Off-white 
Uniform Spheres 
Odor None 
None None Report Odor 
Taste Pass 
Pass Pass None to Slight Bitter 
Bulk Density (g/ml) 
0.625 
0.632 
0.601 
Report Value 
Dissolution Fluid: 
93.0 
83.8 92.5 NLT 80% @ 120 min 
Acid & SIF @ 50 rpm 
Interval 120 mins 
(% Release) 
__________________________________________________________________________ 
Parameter Initial 
1 M 37/75 
2 M 37.75 
3 M 37/75 
6 M 37/75 
Specifications 
__________________________________________________________________________ 
Potency (mg/g) 
761.0 
734.0 766.0 798.0 764.0 658.0-840.0 act/gr 
Potency (% Theory) 
104.2 
105.5 104.9 109.3 104.7 
Potency (% of Initial) 
100.0 
96.5 100.7 104.6 100.4 90.0-115.0% LC 
Loss of Dryness (% loss) 
0.05 
2.17 1.89 1.55 2.47 Report Value 
Water (%) 2.91 
4.40 5.55 4.21 4.75 Report Value 
Appearance Pass 
Pass Pass Pass Pass Free Flowing White 
to Off-white 
Uniform Spheres 
Odor None 
None None None None Report Odor 
Taste Pass 
Pass Pass Pass Pass None to Slight Bitter 
Bulk Density (g/ml) 
0.625 
0.625 0.655 0.631 0.606 Report Value 
Dissolution Fluid: 
93.0 
90.2 93.5 88.4 74.8 NLT 80% @ 120 min 
Acid & SIF @ 50 rpm 
Interval 120 mins 
(% Release) 
__________________________________________________________________________ 
Storage Conditions: 
RT = Room Temperature 15-30.degree. C. 
37/75 = 35-40.degree. C. with 70-80% Relative Humidity 
M = Month 
TABLE 4C 
__________________________________________________________________________ 
Batch: #871109A-1 Batch Size (KG): 1.2 Theoretical Potency (mg/g): 
731.00 
__________________________________________________________________________ 
Parameter Initial 
3 M RT 
6 M RT 
Specifications 
__________________________________________________________________________ 
Potency (mg/g) 
735.0 
786.0 
772.0 
658.0-840.0 act/gr 
Potency (% Theory) 
100.5 
107.5 
105.6 
Potency (% of Initial) 
100.0 
106.9 
105.0 
90.0-115.0% LC 
Loss of Dryness (% loss) 
0.37 
0.64 0.73 Report Value 
Water (%) 2.98 
3.02 3.56 Report Value 
Appearance Pass 
Pass Pass Free Flowing White 
to Off-white 
Uniform Spheres 
Odor None 
None None Report Odor 
Taste Pass 
Pass Pass None to Slight Bitter 
Bulk Density (g/ml) 
0.651 
0.621 
0.590 
Report Value 
Dissolution Fluid: 
90.4 
83.6 83.7 NLT 80% @ 120 min 
Acid & SIF @ 50 rpm 
Interval 120 mins 
(% Release) 
__________________________________________________________________________ 
Parameter Initial 
1 M 37/75 
2 M 37/75 
3 M 37/75 
6 M 37/75 
Specifications 
__________________________________________________________________________ 
Potency (mg/g) 
735.0 
735.0 754.0 780.0 804.0 658.0-840.0 act/gr 
Potency (% Theory) 
100.5 
100.5 103.9 106.7 110.0 
Potency (% of Initial) 
100.0 
100.0 102.6 106.1 109.4 90.0-115.0% LC 
Loss of Dryness (% loss) 
0.37 
1.55 2.05 2.16 2.61 Report Value 
Water (%) 2.98 
3.97 4.77 4.46 3.84 Report Value 
Appearance Pass 
Pass Pass Pass Pass Free Flowing White 
to Off-white 
Uniform Spheres 
Odor None 
None None None None Report Odor 
Taste Pass 
Pass Pass Pass Pass None to Slight Bitter 
Bulk Density (g/ml) 
0.651 
0.644 0.670 0.636 0.617 Report Value 
Dissolution Fluid: 
90.4 
81.3 82.5 82.2 76.2 NLT 80% @ 120 min 
Acid & SIF @ 50 rpm 
Interval 120 mins 
(% Release) 
__________________________________________________________________________ 
Storage Conditions: 
RT = Room Temperature 15-30.degree. C. 
37/75 = 35-40.degree. C. with 70-80% Relative Humidity 
M = Month 
The stability data for all three batches was satisfactory, although it is 
clearly shown that the microgranules manufactured with a 75/25 weight % 
mixture of acetone and methyl alcohol as the solvent for the enteric 
coating composition (Batches 871103C-1 and 871116A-1) had better 
dissolution characteristics than the same microgranules manufactured with 
a 50/50 weight % mixture of acetone and methyl alcohol as the enteric 
coating composition solvent (Batch 871109A-1). 
EXAMPLE 5 
Effect of Percent Enteric Coat Weight on Dissolution and Taste Mask 
Four batches of erythromycin microencapsulated granules were manufactured 
in accordance with the procedure set forth in Example 1 above. However, 
two batches (Batch 871112A and Batch 871113A) received a 4% by weight 
enteric coating and the other two batches (Batch 871116A and Batch 
871117B) received a 6% by weight enteric coating. The differences in 
dissolution and taste mask were compared between the erythromycin granules 
with a 4% by weight enteric coating (Batches 871112A and 871113A) and the 
erythromycin granules with a 6% by weight enteric coating (Batches 871116A 
and 871117B). The results of the comparison are set forth in Table 5 
below. 
TABLE 5 
______________________________________ 
Time 
Batch % Ct. Wt. (min) % Dissolved 
Comments 
______________________________________ 
871112A 
4 90 75.8 Bitter to slight 
120 89.9 Bitter taste 
871113A 
4 90 78.7 Very slight 
120 93.0 bitter taste 
871116A 
6 90 90 No taste 
120 95.0 
871117B 
6 90 79.0 No taste 
120 94.0 
______________________________________ 
Dissolution analysis for enteric coated pellets was performed as follows: 
90 minutes = 60 minutes in SGF and 30 minutes in SIF. 
120 minutes = 60 minutes in SGF and 60 minutes in SIF. 
*Dissolution analysis based on measured potency. 
The 6% by weight enteric coated erythromycin (Batches 871116A and 871117B) 
displayed better dissolution characteristics and better taste mask 
characteristics than the erythromycin granules with a 4% by weight enteric 
coating (Batches 871112A and 871113A). 
EXAMPLE 6 
Granule Dissolution and Taste Mask Properties with Three Protective Coats 
and Methylene Chloride Enteric Coating Formulation 
Microencapsulated granules were prepared in accordance with Example 1 
above. However, the enteric coating composition used to coat the seeds 
comprised 5% by weight hydroxypropyl methylcellulose phthalate in a 
solvent mixture of 75% by weight methylene chloride and 25% by weight 
methanol. 
Dissolution and taste mask were tested for these granules in the same 
manner as in Example 5. The results of these tests are set forth below in 
Table 6. 
TABLE 6 
______________________________________ 
Batch % Ct./Wt. Time (min.) 
% Dissolved 
Comment 
______________________________________ 
871030C 
6 90 85.7* Slight bitter 
120 100.3* to no taste 
______________________________________ 
*Dissolution data based on theoretical potency. 
The dissolution characteristics and taste mask characteristics exhibited by 
the granules of this example were comparable to those exhibited by the 
granules of Example 5 (enteric coating composition with an acetone based 
solvent). 
EXAMPLE 7 
Pharmacokinetic Comparison of Erythromycin Dihydrate Microencapsulated 
Granules and a Conventional Erythromycin Product 
A twelve-hour bioavailability study was performed comparing erythromycin 
microencapsulated granules prepared in accordance with Example 1 above to 
an equivalent dose of a conventional erythromycin formulation, ERYC.RTM. 
(registered trademark of Parke-Davis, Division of Warner-Lambert Company). 
The study was performed in the following manner. 
Twenty-eight subjects were administered a single dose (250 mg) of each 
formulation (erythromycin microencapsulated granules and ERYC.RTM.) in a 
randomized, cross-over food-fasted format with each dose separated by a 
7-day washout period. 
The subjects were healthy male and female volunteers, 21 to 39 years of 
age, and weighed within 10% of ideal body weight. Subjects were determined 
healthy by normal vital organ functions as reflected by medical history, 
physical examination, and laboratory tests. Females had negative serum 
pregnancy tests and were either surgically sterilized or using a reliable 
method of contraception. 
The subjects were administered the erythromycin formulation with one 
teaspoonful of applesauce and 180 ml of water. Subjects with the 
standardized breakfast were administered the erythromycin formulation 
after finishing one Egg McMuffin.RTM. then followed by one hot apple pie 
and the rest of the beverages (orange juice and coffee). 
Five (5) ml of blood were collected prior to erythromycin administration, 
and then at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours after 
administration. The blood was allowed to clot. Serum was separated by 
centrifugation within 60 minutes after collection. A seraclear filter was 
used to clarify the serum. Serum was placed in labelled polypropylene 
tubes and stored frozen at -20.degree. C. 
Erythromycin concentrations were determined by microbiologic assay using 
Micrococcus lutea. An agar well procedure was performed in 10 mm sterile 
plastic petri plates containing Antibiotic Media #1 (Difco.RTM.), adjusted 
to pH 8.5 before sterilization. 
Mean pharmacokinetic parameters were determined from the samples of the 
subjects and are reported below in Table 7A. 
A repeated measures analysis of variance was used to compare the four 
treatment regimens. Tukey's method posthoc multiple comparisons was used 
to compare mean values between two treatment regimens. P values are 
reported below in Table 7B (NS=Not Significant, p&gt;0.05). 
TABLE 7A 
__________________________________________________________________________ 
Mean Pharmacokinetic Parameters 
Regimen A Regimen B 
Regimen C 
Regimen D 
__________________________________________________________________________ 
C.sub.max 
1.23 .+-. 0.58 
1.16 .+-. 0.70 
0.73 .+-. 0.55 
0.50 .+-. 0.24 
T.sub.max 
3.06 .+-. 1.04 
3.18 .+-. 0.89 
5.82 .+-. 1.16 
5.29 .+-. 1.00 
T.sub.lag 
2.02 .+-. 1.20 
2.27 .+-. 0.80 
4.32 .+-. 1.94 
4.33 .+-. 1.17 
Ke 0.424 .+-. 0.098 
0.464 .+-. 0.168 
0.45 .+-. 0.207 
0.446 .+-. 0.129 
Half-Life 
1.72 .+-. 0.40 
1.69 .+-. 0.61 
1.64 .+-. 0.61 
1.73 .+-. 0.66 
AUC.sub.0-12 
3.56 .+-. 1.92 
3.01 .+-. 1.95 
1.77 .+-. 1.40 
1.46 .+-. 1.40 
AUC.sub.0-.infin. 
4.16 .+-. 1.98 
3.69 .+-. 1.95 
2.55 .+-. 1.24 
1.56 .+-. 0.76 
__________________________________________________________________________ 
Note: 
Regimen A = granules without breakfast 
Regimen B = ERYC .RTM. without breakfast 
Regimen C = granules with breakfast 
Regimen D = ERYC .RTM. with breakfast 
TABLE 7B 
______________________________________ 
C.sub.max 
T.sub.max T.sub.lag 
AUC.sub.0-12 
______________________________________ 
A to B NS NS NS NS 
A to C &lt;0.05 &lt;0.05 &lt;0.05 &lt;0.05 
B to D &lt;0.05 &lt;0.05 &lt;0.05 &lt;0.05 
C to D NS NS NS NS 
______________________________________ 
Of the twenty-eight subjects enrolled, 26 completed the required four 
treatment regimens. Statistical significance was defined as a p value of 
0.05. Statistical analysis of AUC.sub.0-12, C.sub.max, T.sub.max, and 
T.sub.lag demonstrated no differences in relative oral bioavailability 
between the microencapsulated granule formulation of the present invention 
and ERYC.RTM. capsule under either fasting or nonfasting conditions. The 
mean AUC.sub.0-12 of Regimen A was 3.56 mghr/L compared to 3.01 mghr/L for 
Regimen B. The mean C.sub.max, T.sub.max, and T.sub.lag of Regimen A were 
similar to Regimen B. The mean AUC.sub.0-12 of Regimen C was 1.77 mghr/L 
compared to 1.46 mghr/L for Regimen D. The mean C.sub.max, T.sub.max, and 
T.sub.lag were also similar. Administration of the microencapsulated 
granule formulation of the present invention or ERYC.RTM. capsule with 
breakfast had a significant effect on relative oral bioavailability of 
both products. A decrease in AUC.sub.0-12 of approximately 50% was seen 
with the granule formulation and ERYC.RTM. capsule A statistically 
significant decrease in C.sub.max was also observed. The time to onset of 
absorption (T.sub.lag) and peak concentration (T.sub.max) were 
significantly prolonged with food. 
Visual inspection of the serum erythromycin concentration v time curves 
demonstrated similar variability in the absorption of both products. In 36 
of 104 concentration vs. time profiles, elimination rate constants could 
not be calculated, as there were inadequate data points clearly in the 
elimination phase. For this reason, statistical analysis of Ke, half-life, 
and AUC.sub.0-12 was not performed. Food also significantly decreased 
C.sub.max and prolonged T.sub.lag and T.sub.max for both products. 
EXAMPLE 8 
Preparation of Microencapsulated Erythromycin Granules with Hydroxypropyl 
Methylcellulose E-5 as a Binder 
Microencapsulated granules were prepared (870102A) in accordance with 
Example 1 above. However, the active coating composition was composed of 
4.5% (w/w) HPMC E-5 30.5% (w/w) Erythromycin and 65% (w/w) Methyl Alcohol. 
The starting seeds used were 40/60 mesh non-pareils. An 8-fold buildup of 
the starting seeds was used to produce the final product. The final 
theoretical potency was about 700 .mu.g/mg (70%). 
Although no attempt was made to use smaller starting seeds (60/80) or to 
perform a 24-fold buildup, this example indicates that HPMC E-5 is almost 
as good a binder as the polyethylene oxide/polyethylene glycol mixture. 
The results of these experiments are shown in Table 8. This binder 
produced yields of better than 90% in the desired size range at each of 
the processing steps (Active I, Active II and Active III). 
EXAMPLE 9 
Preparation of Microgranules of Erythromycin with Hydroxypropyl 
Methylcellulose E-15 as a Binder 
Microencapsulated granules were prepared (870120B) in accordance with 
Example 1 above. However, the active coating composition was composed of 
2.1% (w/w) HPMC E-15, 32.7% (w/w) Erythromycin, 0.42% (w/w)PEG 400 and 
64.8% (w/w) Methyl Alcohol. The starting seeds were 40/60 mesh 
non-pareils. An 8-fold buildup of the starting seeds was intended to 
produce the final product. The results of these experiments are shown in 
Table 8. This binder system did not produce active seeds resilient enough 
to withstand the extended processing time associated with the required 
high potency level. It is possible that alteration of processing 
conditions or the solvent system could improve the results so that a 
product of this nature might be deemed acceptable. 
EXAMPLE 10 
Preparation of Microgranules of Erythromycin with Hydroxypropyl 
Methylcellulose Phthalate HP 55S as a Binder 
Microencapsulated granules were prepared (870305B & 870312B) in accordance 
with Example 1 above. However, the active coating composition was composed 
of 2.8% (w/w) HPMCP HP 55S, 32.3% (w/w) Erythromycin, 52.3% (w/w) Methyl 
Alcohol, and 11.7% w/w Ethyl Acetate. The starting seeds used were 40/60 
mesh non-pareils. An 8-fold buildup of the starting seeds was intended to 
produce the final product. The final theoretical potency was 699 .mu.g/mg. 
The results of these experiments are shown in Table 8. 
This binder produced yields of better than 90% in the desired size range at 
each of the processing steps. However, a high level of residual Ethyl 
Acetate was found (3.4% w/w). Although no attempt was made to use smaller 
starting seeds (60/80) or to perform a 24-fold buildup, this example 
indicates that HPMCP HP 55S is almost as good a binder as the polyethylene 
oxide/polyethylene glycol mixture. When Ethyl Acetate was removed from the 
solvent system, the binder did not produce active seeds resilient enough 
to withstand the extended processing times necessary for the high potency 
level. It is possible that further alteration of processing conditions or 
the solvent system could improve the results so that a product of this 
nature might be deemed acceptable. 
EXAMPLE 11 
Preparation of Microgranule of Erythromycin with Hydroxypropyl Cellulose as 
a Binder 
Microencapsulated granules were prepared (870116C) in accordance with 
Example 1 above. However, the active coating composition was composed of 
2.5% (w/w) HPC, 32.5% (w/w) Erythromycin, and 65% (w/w) Methyl Alcohol. 
The starting seeds used were 40/60 mesh non-pareils. An 8-fold buildup of 
the starting seeds was intended to produce the final product. The results 
of these experiments are shown in Table 8. This binder did not produce 
active seeds resilient enough to withstand the extended processing time 
associated with the required high potency level. It is possible that 
alteration of processing conditions or the solvent system could improve 
the results so that a product of this nature might be deemed acceptable. 
EXAMPLE 12 
Preparation of Microgranules of Erythromycin with a 50/50 Mixture of HPMC 
E-15 and HPC 
Microencapsulated granules (870124B) were prepared in accordance with 
Example 1 above. However, the active coating composition was composed of 
0.95% (w/w) HPMC E-15, 0.95% (w/w) HPC, 39.5% (w/w) Erythromycin, and 
58.6% (w/w) Methyl Alcohol. The starting seeds used were 40/60 mesh 
non-pareils. An 8-fold buildup of the starting seeds was intended to 
produce the final product. The results of these experiments are shown in 
Table 8. This binder system did not produce active seeds resilient enough 
to withstand the extended processing time associated with the required 
high potency level. It is possible that further alteration of processing 
conditions or the solvent system could improve the results so that a 
product of this nature might be deemed acceptable 
EXAMPLE 13 
Preparation of Microgranules of Erythromycin with Polyvinyl-pyrrolidone as 
a Binder 
Microencapsulated granules were prepared (861226B) in accordance with 
Example 1 above. However, the active coating composition was composed of 
4.55% (w/w) PVP K-30, 30.4% (w/w) erythromycin, and 65.0% (w/w) water. The 
starting seeds used were 40/60 mesh non-pareils. An 8-fold buildup of the 
starting seeds was intended to produce the final product. The results of 
this experiment are shown in Table 8. This binder did not produce active 
seeds resilient enough to withstand the extended processing time 
associated with the required high potency level. It is possible that 
alteration of processing conditions or the solvent system could improve 
the results so that a product of this nature might be deemed acceptable. 
TABLE 8 
__________________________________________________________________________ 
% Usable 
% Recovered 
(within 
(amt. of (Stage 
Lot desired 
material 
Solvent 
of 
Example 
Binder No. range) 
discharged) 
System 
Active) 
Comments 
__________________________________________________________________________ 
ACTIVE I 
8 HPMC E-5 
861229A 
93.8 93.9 Methanol 
1 of 3 
9 HPMC E-15 
870115A 
91.5 92.0 Methanol 
1 of 3 
10 HPMCP 
HP 55S 870305B 
93.6 95.3 Methanol/ 
1 of 2 
Ethyl 
Acetate 
(82%/18%) 
11 HPC 870116C 
89.4 89.6 Methanol 
1 of 3 
Did poorly in comparison 
to the other binders 
tested 
12 HMPC E-15/ 
HPC (50/50) 
870124B 
92.5 93.4 Methanol 
1 of 3 
13 PVP 29/32 
861226B 
79.5 81.1 Methanol 
1 of 3 
8 HPMC E-5 
861231A 
94.6 94.6 Methanol 
2 of 3 
9 HPMC E-15 
870120B 
83.1 96.4 Methanol 
2 of 3 
10 HPMCP 
HP 55S 870312B 
94.9 97.1 Methanol/ 
2 of 2 
Ethyl 
Acetate 
(82%/18%) 
11 HPC -- -- -- -- This binder system 
showed inability to 
withstand further 
processing 
12 HMPC E-15/ 
HPC (50/50) -- -- -- -- This binder system 
showed inability to 
withstand further 
processing 
8 HPMC E-5 
870102A 
91.8 96.0 Methanol 
3 of 3 
9 HPMC E-15 -- -- -- -- This binder system 
showed inability to 
withstand further 
processing 
10 HPMCP 
HP 55S -- -- -- -- This binder was used in 
an active process that 
required only two sets 
11 HPC -- -- -- -- This binder system 
showed inability to 
withstand further 
processing 
12 HMPC E-15 
HPC (50/50) -- -- -- -- This binder system 
showed inability to 
withstand further 
processing 
__________________________________________________________________________ 
NOTE: 
The objective of a finished active product is an 8 to 1 weight gain. This 
was accomplished in a three step process with the exception of (HPMCP H 
55S) which required only two steps. Therefor, Active II (HPMCP HP 55S) is 
equivalent to (HPMC E5) Active III. 
EXAMPLE 14 
Effect of Polyethylene Oxide Binder Level in the Absence of Protective 
Coating Layers 
Erythromycin microencapsulated granules were prepared in accordance with 
Example 1. However, in some of the batches, polyethylene oxide alone was 
used as the binder instead of the polyethylene oxide/polyethylene glycol 
mixture. Additionally, the processing of the microgranules was stopped at 
different stages and the granules were tested to determine their 
dissolution characteristics in simulated gastric fluid (SGF) and/or 
simulated intestinal fluid (SIF). Table 9, below shows the results of 
these tests. 
TABLE 9 
__________________________________________________________________________ 
Yield 
Batch 
Stage 
Time 
% Dissolution 
% Ct Wt 
(%) Comments 
__________________________________________________________________________ 
871005C 
Enteric 
90 min. 
34.7 8 69 Act.: 8% binder (Polyox) 
871007A 
Enteric 
90 min. 
34.5 15 97 Act.: 8% binder (Polyox) 
871005A 
Active 
30 min. 
69.4* N/A 96 8% binder (Polyox) 
871008D 
Active 
30 min. 
106.6 N/A 69 5% binder (Polyox) 
871013B 
Active 
30 min. 
94.0 N/A 92 8% binder (Polyox/PEG) 
871017A 
Acitve 
30 min. 
86.6* N/A 95 8% (Polyox/PEG),1 pr. ct 
__________________________________________________________________________ 
Dissolution analysis for the active pellets was performed in SIF only. 
Dissolution analysis for enteric coated pellets was performed as follows: 
90 minutes = 60 minutes in SGF and 30 minutes in SIF 
*Dissolution data based on theoretical potency. All other results based o 
measured potency. 
The results shown above in Table 9 suggest a reaction between polyethylene 
oxide and erythromycin. The percentage of dissolution was unacceptably low 
in all the batches in which an 8% by weight polyethylene oxide binder was 
used (Batches 871005C, 871007A, 871005A). However, the lowering of the 
polyethylene oxide binder to 5% by weight resulted in a dissolution 
improvement, but the seeds were not resilient enough to withstand the 
extended processing time associated with the required high potency level 
as indicated by low values for yield (Batch 871008D). 
Additionally, the mixture of polyethylene oxide and polyethylene glycol as 
a binder at 8% by weight resulted in microgranules with acceptable 
dissolution characteristics (Batch 871013A) but slightly reduced yield. 
The use of a polyethylene oxide/polyethylene glycol protective coating did 
slow the dissolution somewhat (see Batch 871017A) but raised yield 
slightly. 
EXAMPLE 15 
Comparison of Inventive Microgranules to ERYC.RTM. Granules 
Table 10, below, compares the present inventive erythromycin microgranules 
to ERYC.RTM. erythromycin granules. The critical characteristics compared 
are size, potency, sphericity, bulk density and activity density. 
TABLE 10 
______________________________________ 
Inventive Microgranules to 
ERYC .RTM. Granules 
______________________________________ 
Screen Analysis 
Weight Percent 
Larger Than Stated Size 
Mesh Size 14 
16 18 20 25 30 35 
Microns 1410 
Product Name 1190 1000 240 710 590 500 
______________________________________ 
ERYC .RTM. (Erythromycin) 
66.5 29.2 3.1 0.5 0.2 0.1 
Present Invention 5.0 49.0 36.0 8.0 2.0 
(Erythromycin) 
(Batch 870309A) 
______________________________________ 
Potency Spheri- Bulk 
Weight city* Den- Activity 
Product Name % Percent sity Density 
______________________________________ 
ERYC .RTM. (Erythromycin) 
57.3 81.7 0.741 
0.425 
Present Invention 
67.4 90.5 0.668 
0.450 
(Erythromycin) 
(Batch 870309A) 
______________________________________ 
*Sphericity was determined by a "cut and weigh" method. Photomicrographs 
were taken of individual particles. A template was then used to draw a 
circle circumscribing each particle. These circles were then cut out and 
weighed. Subsequently, the outline of the particle itself was cut out of 
the original circle and the remainder weighed. The weight of the remainde 
divided by the weight of the original circle and multiplied by 100 gave 
Sphericity Percent. 
Table 10 indicates that presently available erythromycin granules do not 
meet all the required specifications of the present invention. 
While the invention has been disclosed by reference to the details of 
various embodiments of the invention, it is understood that this 
disclosure is intended in an illustrative rather than in a limiting sense, 
as it is contemplated that modifications will occur to those skilled in 
the art, within the spirit of the invention and the scope of the appended 
claims.