Sustained release formulations

Semi-enteric controlled release formulations are comprised of a biological active agent such as an antibiotic that is blended with a water-soluble bulking agent, the mix then coated onto an inert core. The coated active core is further coated with a mixture comprised of an acrylic copolymer, bulking agent and pH dependent food acid. These different coating components possess different solubility characteristics which result in a gradual release of the active in both the stomach and small intestine that provides an increased bioavailability of the active drug.

FIELD OF THE INVENTION 
The present invention relates to pharmaceutical preparations and the 
controlled, sustained release thereof. In particular, the present 
invention concerns the sustained release of an antibiotic such as 
doxycycline hyclate over a period of time after oral administration so 
that the drug is completely absorbed into the patient's system. The 
pharmaceutical composition comprises a coated, inert sphere or pellet that 
initially begins a partial breakdown and absorption of the drug in the 
stomach with complete release and absorption in the small intestine. 
BACKGROUND OF THE INVENTION 
Many pharmaceutical delivery systems are known in the art which are 
designed to either delay the release of the drug until the system reaches 
a particular region of the digestive tract or they are designed to 
gradually release the drug immediately after oral administration. Enteric 
formulations are designed to prevent any release of the drug for 
bioavailability until the delivery system reaches the intestine. These are 
generally designed for those pharmaceuticals that cause stomach irritation 
or distress. 
Normally, pharmaceuticals that are highly soluble irrespective of the pH of 
the surrounding environment can be formulated into sustained release 
delivery systems relatively easily. The delayed release properties can be 
attained by several methods. On the one hand, the drug can be embedded 
into a matrix of other excipients which are relatively water insoluble and 
hence, dissolve slowly so as to release the drug to the digestive system 
slowly. Another method is to shape the drug and excipients into granules 
or pellets as an active core which are then coated with a substance that 
dissolves slowly. Usually, these methods produce a delivery system that 
dissolves either entirely in the stomach or intestine but not both. 
The other drawback with many of these sustained release delivery systems 
known in the art is the fact that not all of the drug becomes bioavailable 
during its passage through the digestive tract and it eventually becomes 
lost and expelled through the feces. Attempts have been made to get around 
these problems by mixing the drug with an excipient and then either 
forming a core material comprised of the drug excipient mixture or by 
coating an inert core such as a non-pareil seed with the drug/excipient 
mixture followed by a coating of the entire pellet with a thin polymer 
film. 
A major problem in the coating of the core granules by the methods of the 
prior art is the need to dissolve the coating materials in organic 
solvents prior to their application. These solvents are not only expensive 
but dangerous in that they are highly explosive. They also pose health and 
environmental problems in that most are highly toxic. 
U.S. Pat. No. 4,138,475 to McAinish et al discloses a sustained release 
formulation for propranolol or pharmaceutically acceptable salts thereof 
whereby the drug is mixed with non-water swellable microcystalline 
cellulose and formed into spheroids. These are then coated with a heavy 
film of hydroxypropyl methyl cellulose (HPMC) and or a plasticizer which 
prevents any release of the drug in the stomach. Needless to say, not all 
of the drug becomes bioavailable in the small intestine either. 
U.S. Pat. No. 4,837,030 to Valorose et al discloses a sustained release 
delivery system for tetracycline compounds designed to release a minor 
amount of the drug slowly in the human stomach and then rapidly release 
the remainder in the small intestine. This is accomplished by mixing the 
drug with one or more of a number of excipients such as microcrystalline 
cellulose, polyvinylpyrrolidone (PVP), carboxymethyl cellulose, etc., and 
a binder such as gelatin which is then either extruded into a spherical 
pellet or coated about a non-pareil seed. The pharmaceutical core pellet 
may then be coated with a thin polymer or left bare; in either case it is 
only 60-90% released in the course of its passage after ninety (90) 
minutes. 
U.S. Pat. No. 4,832,958 to Baudier et al reveals a galenic form of 
prolonged release verapamil and its salts by mixing the drug with a 
wetting agent such as fatty acid esters, lecithin, sucrose, mannitol or 
sorbitol and then spheronizing or granulating the mixture into 
micro-granules. These are then coated with a microporous membrane 
comprised of a polymer such as Eudragit.RTM. E30D, (Rohm Pharma GmbH, 
Weiterstadt, West Germany), HPMC phthalate and other wetting agents, 
plasticizers and the like. The formulations are designed to withstand 
adverse environmental conditions during storage such as high temperatures. 
The formulation is enteric by nature and the drug does not become 
bioavailable until the system reaches the small intestine. 
U.S. Pat. Nos. 4,795,644 and 4,418,183 to Zentner disclose delivery systems 
for the controlled release of drugs that is not pH-dependent through the 
modulation of the release of a core drug through a microporous wall 
coating using charged, insoluble resins that bear an electrostatic charge 
that is identical to that of the drug. The charged resin is water 
insoluble and non-diffusible through the microporous wall while the active 
drug is diffusible and water soluble. The charged resins may be either 
anionic or cationic in nature, and include polystyrene, epoxy-amine 
phenolic or methacrylic backbones and release the drug through the 
microporous wall according to the osmotic pressure, not the pH of the 
external environment. This allegedly allows for the tailoring of a whole 
range of release rates according to the type of drug used. 
U.S. Pat. No. 4,438,091 to Gruber et al discloses a composition for the 
delayed release of bromhexine comprised of a mixture of the 
bronchodialator with an acid such as fumaric or tartaric acid which is 
compressed into a spherical tablet and coated with lacquers that are 
insoluble in gastric juices and soluble in intestinal juices. These 
comprise copolymers of acrylic acid and methacylic acid esters. Whereas 
the drug is generally insoluble at the higher pH values of the intestine 
and would be absorbed too quickly at the lower acidic pH conditions of the 
stomach, the acidic matrix prevents quick dissolution early and yet 
promotes the drugs bioavailability further downstream in the digestive 
tract. 
European Patent Appln. No. 0,035,780 to Sekigawa et al discloses a process 
for the preparation of enterosoluble drugs by coating a solid dosage form 
of the drug with hydroxypropyl methylcellulose phthalate or acidic 
succinyl and acetyl esters of HPMC. Triethylcitrate is added as a 
plasticizer which aids in the binding of the coating material to the core 
pellet. The coating then resists dissolution in the stomach but completely 
dissolves in the small intestine. 
European Patent Appln. No 0,273,005 to Ventouras discloses a water 
dispersible tablet comprised of an active pharmaceutical core material, a 
pH dependent disintegrant such as crospovidone (N-vinyl-2-pyrrolidone) or 
croscarmellose and a water-swellable agent such as guar gum, alginates, 
dextran and the like. Once contacted by moisture in the human oral cavity, 
the swellable material absorbs water and becomes gel-like, aiding passage 
through the oral cavity and throat. Once the delivery system reaches the 
acidic pH of the stomach, the disintegrant breaks apart immediately, 
releasing the drug for complete bioavailability. 
None of the aforementioned formulations however, are truly semi-enteric 
formulations whereby the active pharmaceutical is dispersed slowly and 
continually from the early stages of the digestive tract throughout its 
passage in the stomach and small intestine so as to become 100% 
bioavailable. Moreover, none of the prior art references and formulations 
provide for the gradual and controlled release of an active pharmaceutical 
whose bioavailability is evenly distributed over time. 
It is an object of the present invention to provide a controlled, 
semi-enteric formulation of an active pharmaceutical that is slowly and 
continually dissolved and absorbed throughout its passage through both the 
gastric and intestinal portions of the digestive system. More specifically 
it is an object of the present invention to provide an antibiotic 
formulation that is quasi-enteric in nature, i.e., that is partially 
bioavailable in both the stomach and the small intestine so as to insure 
100% bioavailability in both. In particular, it is an object of the 
present invention to provide a semi-enteric formulation for an antibiotic 
which becomes bioavailable throughout its passage in the digestive tract. 
SUMMARY OF THE INVENTION 
Semi-enteric sustained release pharmaceutical compositions provide for the 
controlled release of a biological active material such as an antibiotic 
in both the stomach and small intestine for increased bioavailability. The 
semi-enteric release is made possible by initially mixing the active drug 
with a water soluble bulking agent. This mixture is uniformly coated about 
an inert core material such as a non-pareil seed. This is then further 
coated with a blend of a methacrylic acid copolymer, a water soluble 
bulking agent and a food grade acid whose solubility is pH dependent. 
Since the pH conditions of the stomach and small intestine differ, the 
coating materials become soluble at different points in the digestive 
tract. The water soluble bulking agent will begin to break down in the 
hydrous environment of the stomach resulting in the partial release of 
some of the active core. The copolymer and the pH dependent food acid do 
not dissolve until the pharmaceutical composition enters the more basic 
environment of the small intestine. Hence, a controlled sustained release 
of the biological active is achieved throughout both the stomach and 
intestine thereby resulting in increased bioavailability of the drug.

DETAILED DESCRIPTION OF THE INVENTION 
The drug delivery system of the present invention utilizes a unique 
combination of coating materials that result in a controlled, semi-enteric 
formulation of the drug that releases throughout the digestive system to 
insure 100% bioavailability of the active agent. The controlled sustained 
release of the drug is due to different solubility characteristics of the 
coating materials which dissolve or break down in different parts of the 
digestive tract resulting in a gradual, partial release of the drug over 
time. 
The drug is initially mixed with a water soluble bulking agent to form an 
active matrix that is then uniformly coated about an inert, non-pareil 
sugar seed. This core is then coated with a mixture of materials that 
ultimately control release of the drug to the system. The major coating 
constituent is a methacrylic acid copolymer commercially known as 
Eudragit.RTM. L30D, a film forming polymer in an aqueous solid dispersion 
made by Rohm Pharma Gmbh, Weiterstadt, West Germany. In the past, 
Eudragit.RTM. L30D was employed to prepare fully enteric pharmaceutical 
formulations. Drugs that are coated with this polymer are not released to 
the system under the pH conditions existing in the stomach but rather are 
released when the polymer dissolves under the pH conditions of the 
intestine. In the present invention, the release characteristics of the 
Eudragit L30D polymer are modified so that a semi-enteric formulation is 
developed. 
In order to modify the dissolution characteristics of Eudragit.RTM. L30D, a 
water soluble bulking agent such as a sugar alcohol is mixed with the film 
forming polymer. Suitable sugar alcohols useful in the practice of the 
present invention include mannitol, sorbitol, lactitol and the like. 
Mannitol is the preferred bulking agent in that it will dissolve and break 
down in any hydrous environment, irrespective of the pH. Another 
constituent of the coating is a pH- dependent acid such as fumaric acid 
which will only dissolve and break down in environments with a pH of 
greater than 3.5. Other suitable food grade acids include malic acid, 
citric acid, tartaric acid, ascorbic acid and mixtures thereof. Fumaric 
acid has a very low solubility in water and hence its dissolution will 
only be triggered by the basic conditions existing in the intestine. 
The incorporation of the water soluble bulking agent and the pH dependent 
acid into the Eudragit.RTM. polymer coating allows for a controlled drug 
release to be attained in pH regions where there is usually no drug 
release. This is especially useful for those drugs that irritate the 
stomach since they do permit some release so as to insure 100% 
bioavailability without releasing all the drug so as to cause gastric 
distress. As the bulking agent initially dissolves in the hydrous acidic 
environment of the stomach, small holes appear in the otherwise uniform, 
intact coating. The pharmaceutical is gradually released through these 
holes until the delivery system finally reaches the small intestine where 
the more basic conditions dissolve and break down both the pH dependent 
food grade acid and the methacrylic acid copolymer coat. With the systems 
entry into the more basic environment of the gastrointestinal tract i.e., 
above 3.5, the pH dependent food acid portion will dissolve and more holes 
or spots will appear in the methacrylic acid copolymer coat releasing more 
drug to the system at a greater rate for absorption. Finally, after 
several minutes of exposure of the methacrylic acid coat to the basic 
environment of the small intestine, the methacrylic acid copolymer coating 
breaks down altogether releasing all of the remaining active drug to the 
system for absorption. The polymer portion of the matrix coating starts to 
dissolve at pH 6.0. 
Other excipients are added to the polymer coating in minor amounts in order 
to stabilize the composition and to help bind the system together. 
Plasticizers such as triethyl citrate are added in amounts of up to about 
1.5% in order to aid in the flowability of the coating mixture so as to 
insure maximum uniformity and integrity of the coating. An anti-adherent 
such as kaolin or talc in amounts of up to about 3.0% is also added as an 
inert aid in the stability of coating process. Binders such as 
hydroxypropylcellulose in amounts of from about 0.01 to about 4.0 may also 
be added to hold the various constituents together. 
Whereas the delivery system of the present invention could be tailored to 
provide a semi-enteric carrier for nearly any active pharmaceutical of 
choice, the system has proven most effective in the delivery of 
antibiotics such as doxycycline hyclate, minocycline, oxytetracycline, 
chlortetracycline, demechlorcycline, methycycline their pharmaceutical 
salts and mixtures thereof. In a preferred embodiment of the present 
invention, the pharmaceutical employed is doxycycline hyclate, an 
antibiotic with the following structure: 
##STR1## 
This bacteriostatic compound is effective against a wide variety of 
gram-negative and gram-positive species and is useful in the treatment of 
Rocky Mountain Spotted Fever, venereal disease etc. The drug can be 
incorporated into the delivery system in amounts of from about 20% to 
about 65% w/w, preferably 55%-60% w/w. 
The following examples are provided to more fully describe and delineate 
that which is considered to be the invention. While it is understood that 
minor variations and/or alterations in the materials or process parameters 
may be practiced, it is therefore recognized that said examples are for 
illustration only and should not be construed as limiting the spirit and 
scope of the invention as later recited in the claims. 
EXAMPLE 1 
Doxycycline hyclate cores were prepared by a powder layering technique 
using the CF Granulator manufactured by Freund--Chemical Ltd, Tokyo, 
Japan. One (1) kg. of the drug was passed through a Fitzmill NOOO screen. 
110 gm. of mannitol and 1 gm. of silicon dioxide (SiO.sub.2) were blended 
together then passed through a U.S. standard mesh no. 100 screen. This 
blend was then mixed with the milled drug. The final blend was then 
layered onto 500 gm. of sugar spheres (mesh size 20-25) using 
hydroxypropylcellulose 8% w/w solution as a binder. The layering 
granulator conditions were: 1.0 bar atomization; rotor at 160 rpm; a 
powder delivery rate of 10 rpm; a spray rate of 8 ml./min at 24.degree. C. 
ml/min; product temp. 24.degree. C. The cores were then dried in an oven 
at 45.degree. C. overnight. 
The active antibiotic cores were coated using a Glatt GPCG3 machine Glatt 
Air Techniques, Inc., N.J. The coating system employed consisted of 
Eudragit.RTM. L30D (30% w/w) 41% w/w; triethyl citrate 1.3% w/w; kaolin 
2.4% w/w; mannitol 1% w/w; fumaric acid 0.25% w/w water q.s. to 100% w/w. 
500 gm. of doxycycline hyclate cores were coated to 6% coating level. The 
coated pellets were dried in the machine for 45 min at an inlet temp. of 
45.degree. C. and product temp. 34.degree. C.