Sustained release pharmaceutical compositions in oral dosage form

Oral dosage forms for neutral, zwitterions or slats of acidic or basic drugs with approximate zero order release kinetics comprise a core matrix of the drug, and a gelling polymer, the matrix being coated with a water permeable but insoluble polymer.

SUMMARY OF THE INVENTION 
This invention is concerned with a sustained release oral dosage form for 
medicaments wherein the dosage form has approximate zero-order release 
characteristics, whereby plasma levels of the medicament tend to remain 
largely constant for an appropriate time. The dosage form comprises a 
coated matrix of the medicament in a cellulosic gelling agent. The coating 
constits of a water permeable, but low solubility polymer such as a 
derivatized cellulose which may be the same as or different from the core 
polymer and which provides an initial delay before main release of 
medicament. The formulation of this invention may also contain a buffer to 
maintain the release rate of an acidic or basic drug independent of pH as 
the dosage form moves through the alimentary canal. 
BACKGROUND OF THE INVENTION 
Oral dosage forms for the sustained release of drugs from water insoluble 
and slowly soluble matrices are well known in the prior art such as U.S. 
Pat. No. 4,389,393 and the release is known to occur by a diffusion 
process. As the diffusion path length increases with time, a linear plot 
of percent released versus t.sup.1/2 is obtained which is not ideal for 
maintenance of a plasma level which is intended to be more or less 
constant for an appropriate time. 
Similarly, matrix systems usually exhibit an initial rapid release (but 
"burst" effect) of active ingredient which promotes increased plasma 
levels and may cause the adverse reactions which the dosage form was 
designed to minimize. 
U.S. Pat. Nos. 4,505,890 and 4,610,870 describe controlled release 
formulations having a core containing gelling agent and a coat comprising 
either a film-forming agent and plasticizer or a hydrophilic polymer and a 
hydrophobic polymer. However in thos formulations, the core contains 
either from 8-14%, or from 5-15% of gelling agent. 
With the present invention the "burst" effect has been eliminated by 
providing the matrix with a coating material that provides an additional 
barrier to diffusion of water into the matrix and drug solution out of the 
matrix to the external environment.

DETAILED DESCRIPTION OF THE INVENTION 
The invention provides a sustained release pharmaceutical composition in 
oral dosage form which comprises: (1) a core matrix containing at least 
20% of a derivatized cellulosic gelling agent, a medicament homogeneously 
dispersed therein and optionally pharmaceutically accetable excipients; 
and (2) a coating alyer surrounding the core matrix, the coating material 
being a slowly soluble, water ermeable derivatized cellulosic polymer. 
The derivatized cellulosic gelling agents useful as the core matrix in the 
novel dosage form of this invention include: methycellulose, such as 
Methocel.RTM. A4M (Dow Chemical Co.); hydroxypropylmethylcellulose, (HPMC) 
suh as Methocel.RTM. E4M, F4M, or K4M (Dow Chemical Co.); or 
hydroxypropyl-cellulose (HPC). 
The preferred polymer for use as the matrix is a 
hydroxypropylmethylcellulose, especially with a viscosity of about 4000 
centipoises for a 2% w/v aqueous solution at 20.degree. C., for example 
Methocel.RTM. K4M. 
The coating layer polymer does not contain any medicament. It may comprise 
any of the above described gelling agents compressed onto the core. 
Preferably however the coating layer is a water permeable, water insoluble 
film forming agent, such as ethyl cellulose or cellulose acetate 
phthalate; or acrylic resins such as the copolymers of acrylic and 
methacrylic acid esters. The preferred polymer for use as a coating 
material is ethylcellulose applied as a dispersion. 
Examples of drugs useful in the novel formulations are 
(+)-trans-1a,2,3,4a,5,6-hexahydro-9-hydroxy-4-(1-propyl)-4H-naphth[1,2-b]- 
1,4-oxazine, enalapril, amitriptyline, cyprophetadine, cyclobenzoprine, 
timolol, propranolol, betaxolol, indomethacin, sulindac, diflunisal, 
ibuprofen, and norfloxacin. 
The medicaments useful in the novel formulation of this invention may be 
weak bases, such as primary or secondary amines, or weak acids, such as 
carboxylic acids and their salts. The salts of the weak bases are 
preferably acid addition salts with strong acids such as hydrochloric, 
hydrobromic, phosphoric, sulfuric or maleic acid. The salts of the 
carboxylic acids are normally sodium or potassium salts. Where appropriate 
the active ingredient may be in zwitterionic form e.g. as an internal salt 
or betaine. 
Medicaments which are weak acids or bases and their salts display an 
aqueous solubility that in most cases is dependent on the pH of the 
aqueous environment. Thus as the pH of the gastrointestinal tract varies 
from 1 to 7.5, the solubility of the medicament and consequently its 
release from the prior art dosage forms will vary depending upon its 
position in the alimentary canal and time after administration. 
In a further aspect of this invention, the pH dependent release is 
eliminated by including a buffer in the core matrix. This produces a 
microenvironment of constant pH whereby the solubility of the drug is 
unchanged regardless of the pH of the body fluids of the external 
environment. 
Buffering agents useful with the salts of basic drugs include, for example, 
citric acid, tartaric acid, succinic acid, maleic acid, and fumaric acid. 
A preferred buffer is citric acid. 
Buffering agents useful with salts of the acidic drugs include, for 
example, tromethamine. 
The optional pharmaceutically acceptable exceipients assist in the 
manufacture of the novel formulations and include conventional materials 
such as lactose, magnesium stearate, talc, and sorbitol. 
The novel formulation conveniently weighs about 50 to 1000 mg, for example 
100 to 400 mg. The core comprises about 20 to 60%, and prferably about 30 
to 60% by weight of polymer, the remainder being up to 50% of medicament, 
for example from 0.41 to 20% w/w mg of active ingredient, and from 2.08 to 
12.5% w/w of buffer plus inert excipients. 
The coating may conveniently be applied either by compression or by 
spraying. For a compression tablet, the coating may comprise 30 to 100% of 
the weight of the core, preferably about 50% w/w. This may tpically 
represent 50-100 mg of coating material. When a film forming coating layer 
is employed, the coat may comprise from 2 to 6% of core weight, preferably 
from 3 to 5%. This may typically represent a weight of coating of from 2 
to 10 mg. 
In use, the coating layer of the product of this invention avoids the 
initial burst of release of medicament by providing an initial barrier to 
surface diffusion of medicament. Because the coating layer is water 
permeable, water and gastric fluid is able to permeate through the coating 
layer causing swelling of the core and dissolution of the medicament 
therein. During this initial period, usually approximately 1-2 hours, a 
small amount of mediament diffuses out at a slow rate, through the 
coating, hence providing the initial slow release. When a film-forming 
coating layer is employed, then as the gellation increases, the core 
expands until the coating material is ruptured. At this stage release is 
caused solely by diffusion from the gelled core matrix. If the coating 
comprises a gelling agent, the medicament diffuses into the coating layer 
and is subsequently released therefrom. 
The formulations of the inventions are illustrated by the following 
Examples. In the following examples the medicament is the direct acting 
dopaminergic agent, 
(+)-trans-1a,2,3,4a,5,6-hexahydro-9-hydroxy-4-(1-propyl)-4H-naphth[1,2-b]- 
1,4-oxazine hydrochloride (I). Its use and the use of particular polymers, 
buffers, and inert additives and fillers in the particular amounts shown 
are not intended to limit the scope of this invention but are exemplary 
only. Other basic or acidic drugs and their salts, neutral or zwitterionic 
compounds and other polymers, buffers and inert additivies and fillers 
with similar properties can be used. 
All matrix formulations, independent of potency were manufactured by the 
following general technique. 
Compound I, HPMC K4M and lactose are mixed in a suitable blender. Citric 
acid is dissolved in a suitable volume of ethanol or water and added with 
mixing to the drug owders to obtain a suitable granular consistency. The 
mass is screened, dried, re-screened, lubricated with magnesium stearate 
and compressed on 10/32" (7.9 mm) punches. 
EXAMPLE 1 
core Formulae and Their Release Characteristics 
______________________________________ 
(a) Compound I 1.0 mg 
Citric Acid 10 mg 
HPMC K4M 80 mg 
Lactose 108 mg 
Magnesium stearate 1 mg 
Total 200 mg 
______________________________________ 
Time (hrs) 
Cumulative % dose released at pH 1.2 
______________________________________ 
2 46 
4 63 
6 81 
8 90 
(b) Compound I 5 mg 
Citric Acid 10 mg 
HPMC K4M 80 mg 
Lactose 104 mg 
Magnesium stearate 1 mg 
Total 200 mg 
______________________________________ 
Cumulative % dose released 
Time (hrs) 
pH 1.2 pH 5.5 pH 7.5 
______________________________________ 
2 37 39 31 
4 56 56 57 
6 71 71 69 
8 85 80 79 
10 91 91 85 
(c) Compound I 5 mg 
Citric Acid 5 mg 
HPMC K4M 80 mg 
Lactose 109 mg 
Magnesium stearate 1 mg 
Total 200 mg 
______________________________________ 
Cumulative % dose released 
Time (hrs) pH 1.2 pH 7.5 
______________________________________ 
2 41 43 
4 61 64 
6 77 80 
8 86 91 
10 91 96 
(d) Compound I 10 mg 
Citric Acid 10 mg 
HPMC K4M 80 mg 
Lactose 99 mg 
Magnesium stearate 1 mg 
Total 200 mg 
______________________________________ 
Cumulative % dose released 
Time (hrs) pH 1.2 
______________________________________ 
2 45 
4 68 
6 80 
8 90 
(e) Compound I 24 mg 
Citric Acid 5 mg 
HPMC K4M 80 mg 
Lactose 90 mg 
Magnesium stearate 1 mg 
Total 200 mg 
______________________________________ 
Cumulative % dose released 
Time (hrs) pH 1.2 pH 7.5 
______________________________________ 
2 38 45 
4 60 70 
6 77 82 
8 89 91 
10 95 96 
______________________________________ 
(f) The Effect of Polymer Content on Release Characteristics T1 -HPMC 
content (% w/w) -20 30 40 60 -Compound I 5 mg 5 mg 5 mg 5 mg -HPMC K4M 40 
mg 60 mg 80 mg 120 mg -Lactose 144 mg 124 mg 104 mg 64 mg -Citric Acid 10 
mg 10 mg 10 mg 10 mg -Magnesium Stearate 1 mg 1 mg 1 mg 1 mg -Total 200 mg 
200 mg 200 mg 200 mg- Cumulative % dose released at pH 1.2 -Time (hrs) 
20% 30% 40% 60% -2 58 48 44 36 - 4 82 74 66 54 - 6 98 90 81 68 - 8 100 98 
91 80 - 10 -- 100 97 87 - 
(g) The Effect of Tablet Size on Release Characteristics 
The composition described in Example 1.(b) above was prepared and the 
granulation compressed at 100, 200 and 400 mg on 7/32" (5.6 mm), 10/32" 
(7.9 mm) and 13/32" (10.3 mm) punches respectively. 
______________________________________ 
Cumulative % dose released at pH 1.2 
Time (hrs) 
7/32" 10/32" 13/32" 
______________________________________ 
2 48 40 37 
4 74 60 56 
6 87 79 71 
8 91 89 82 
10 94 95 90 
______________________________________ 
EXAMPLE 2 
Coating Formulae Applied to Cores 
______________________________________ 
(a) Core 
Compound I 5 mg 
Citric Acid 5 mg 
HPMC K4M 40 mg 
Lactose 49.5 mg 
Magnesium stearate 
0.5 mg 
Total 100 mg 
Coat 
HPMC K4M 80 mg 
______________________________________ 
The granule was prepared as described earlier and compressed on 1/4" (6.4 
mm) normal concave punches. The HPMC K4M coat was applied by compression 
using 5/16" (7.9 mm) normal concave punches. 
______________________________________ 
Time (hrs) 
Cumulative % dose released at pH 1.2 
______________________________________ 
2 2 
4 12 
6 32 
8 53 
10 71 
12 84 
______________________________________ 
Release rate approximated to zero-order from 2-12 hours of the profile. 
______________________________________ 
(b) Core As in Example 4.(a) 
Coat HPMC K4M 60 mg 
Time (hrs) 
Cumulative % dose released at pH 1.2 
______________________________________ 
2 12 
4 35 
6 58 
8 77 
10 88 
12 93 
______________________________________ 
Release rate approximated to zero-order over the first hours of the 
profile. 
______________________________________ 
(c) Core 
______________________________________ 
Compound I 5 mg 
Citric Acid 10 mg 
HPMC K4M 80 mg 
Lactose 104 mg 
Magnesium stearate 
1 mg 
Total 200 mg 
______________________________________ 
The granule was prepared as described earlier and compresed on 5/16" (7.9 
mm) concave punches. 
______________________________________ 
Coating 
______________________________________ 
Aquacoat* 372 g 
Dibutyl sebacate 28 g 
______________________________________ 
*An aqueous dispersion of ethylcellulose containing 30% solids. 
The suspension was prepared using conventional mixing equipment and applied 
to the tablets using the air-suspension method. A coat weight of 8 mg per 
tablet was applied. 
______________________________________ 
Time (hrs) 
Cumulative % dose released at pH 1.2 
______________________________________ 
2 13 
4 33 
6 51 
8 67 
10 83 
12 87 
______________________________________ 
Release rate approximated to zero-order over the first 10 hours of the 
profile. 
______________________________________ 
(d) Core As in Example 4.(c) above. 
Coating Aquacoat 77 g 
Myvacet 9-40 7 g 
Water 78 g 
______________________________________ 
Myvacet 9-40 is a distilled acetylated monoglyceride plasticiser available 
from Eastman Chemical Products of Tennessee, U.S.A. 
The coating procedure was as described above. A theoretical coat weight of 
4 mg per tablet was applied. 
______________________________________ 
Cumulative % dose released 
Time (hrs) pH 1.2 pH 5.5 pH 7.5 
______________________________________ 
2 25 26 39 
4 41 49 62 
6 62 67 76 
8 77 81 85 
10 87 92 90 
12 93 100 92 
______________________________________ 
The pH dependence has little in vivo significance and is a function of the 
pH solubility profile of the coat. Under in vivo conditions release will 
initiate shortly after ingestion at about pH 1 and the "burst effect" will 
consequently be eliminated. A pH of 7-7.5 will not be achieved until 4 to 
5 hours after dosing and if the rates are examined after this period they 
are seen to be essentially independent of pH. 
(e) The Effect of Matrix Polymer Content on Release Characteristics of 
Coated Tablets 
Core Formulae: As in Example 1(f) above 
Coating: As in Example 2(d) above 
The coating procedure was as described above. A theroretical coat weight of 
5.5 mg per tablet was applied. 
______________________________________ 
Cumulative % dose released at pH 1.2 
HPMC Content (% w/w) 
Time/Hrs 30% 40% 60% 
______________________________________ 
2 12.3 25.4 26.6 
4 -- 40.9 -- 
6 -- 62.2 -- 
8 -- 77.2 -- 
10 83.7 86.5 81.0 
12 92.1 92.7 88.6 
______________________________________ 
Flexibility in modifying the release profile can be achieved by altering 
the polymer contents of the tablet core and coat.