CA1073358A - Sustained release formulations - Google Patents

Abstract

Abstract A novel sustained release formulation for oral administration in solid dosage forms such as tablets and capsules is disclosed. The formulation is hydrodynamically balanced to be buoyant in gastric juice thereby remaining in the stomach for an extended period of time.

Description

10'~3~5~3 The present invention is concerned with a swstained release pharma-ceutical formulation containing as the active ingredient a benzodia~epine selected from the group consisting of chlordiazepoxide and diaæepam, one or more antacid compounds or acetylsalicylic acid, said formulation being hydro-dynamically balanced so that, upon contact with gastric fluid, said formula-tion acquires and maintains a bulk density of less than 1 thereby being buoyant in said fluid and remaining buoyant in the gastric fluid of the stomach until substantially all of the active ingredient contained therein has been released, said formulation comprising a homogeneous mixture of said ac-tive ingredient; from 0 % to 80 % by weight of therapeutically iner~, pharma-ceutically acceptable adjunct materials; from 0 ~ ~o 60 ~ by weight of a fatty material haYing a specific gravity of less than 1 and from 20 % by weig~t to 75 % by weight of one or a mixture of hydrocolloids selected from the group consisting of methyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose, hydroxyethylcellulose and sodium-carboxy~ethylcellulose to provide upon contact wi~h gastric fluid, a water-impermeable barrier on the surface of said formulation.
The convenience of administering a single dose of medica-

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tion which releases active ingredient over an extended period of time as opposed to the administration of a number of single doses at regular intervals has long been recognized in the pharmaceutical art. T~e advantage to the patient and clinician in ha~ing consistent and uniform blood levels of medication over an extended period of time are likewise recognized. In most sustained release preparations known to the pharmaceutical D art, medicinal agents are either coated with varying of some type of relatively insoluble material or are imbedded into a rigid lattice of resinous material. In such preparations, the object is to continuously provide drug for absorption into the blood stream to replace the amount eliminated while the dosage form is passing through the gastrointestinal tract of the patient.

The conventional approaches to sustained release formula-tion briefly outlined above can be disadvantageous in that certain classes of active ingredients are not suited to absorption during passage through the gastrointestinal tract due to their physiochemical properties and/or favorable sites of absorption. For example, most acidic medicaments are principally absorbed from the stomach, whereas most basic medicaments are absorbed primarily from the intestines. Most medicaments will undergo varying degrees of change in solubility by passage from the acutely acidic conditions of -the stomach to the neutral to alkaline conditions of the intestines. For example, ferrous salts are more soluble in the stomach than in the intestines. Finally, there are medicaments, e.g., antacids, ':

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which are intended to act in the stomach and therefore lose most beneficial properties when they pass into the intestines.

It is readily apparent in view of the above considerations that a large number of medicaments are not amenable to conventional sustained release formulations which are not retained in the stomach and which release medicament in the intestines. It is equally apparent that a sustained release formulation which is retained in the stomach and which slowly releases medicament in the stomach over an extended period of time would be eminently suited to such medicaments. Such a sustained release formulation is provided by the present inven-tion.

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C~/ar~c~e~ s The principle of sustained release which-~k~e4ei~4 the pharmaceutical formulation of the subject invention is ~re~G~/~S
unique in the art, i.e., the formulation rem~in buoyant and free floating in the gastric fluid for an extended period of time, during which substantially all of the medicament is released therefrom. Although many mechanisms of sustained release are recognized in the art and the concept of a floating formulation is recognized, there is no teaching which recognizes the application of buoyancy to sustained release as is taught by the subject invention.

For example, Davis U.S. Patent 3,418,999 teaches a tablet which is buoyant. However, the buoyancy of the tablet is disclosed as being merely an adjunct to swallowing and there is .. : . ~ . ~ . . . ,~ . .
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no suggestion therein of applying the buoyancy to sustained release. The Davis tablets also must have an initial density of less than 1, whereas the tablets of the subject invention are not so restrictedl;l The concept of a tablet which swells when in contact with gastxic fluid is also recognized in the art. For example, Johnson et al. U.S. Patent 3~574,820 teach tablets which swell in contact with gastric fluids to a size such that they cannot pass the pylorus and therefore are retained in the stomach. It is readily apparent that such tablets are not buoyant since, if they were, their size in relation to being able to pass the pylorus would be of no consequence.

The incorporation of a swellable hydrocolloid in a sustained release tablet is also recognized in the art. Playfair U.S. Patent 3,147,187 teaches incorporation of a swelling gum or proteinaceous material into a sustained release tablet to r~ ~/5~egfa f~v~
aid in ~i~tintogration of the tablet and thus expose more surface to digestion. There is no indication that the disclosed tablets are intended to be buoyant. This is further evidenced by the fact that all ingredients are combined into a melt which is thereafter cooled and granulated. The hydrocolloid is therefore formulated in the manner of a conventional tabletting binder as opposed to being added to the formulation in a dry prc?e*ce ";,S
particulate form as in the ~W;U~M~ of the subject invention ^ 25 whereby it functions to facilitate the buoyancy of the tablet.

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Finally, Christenson et al. U.S. Patent 3rO65,143 teach the use of a hydrocolloid in a sustained release tablet to form a water impermeable barrier on the outer surface of the tablet which gradually erodes and thus releases medicament over an extended period of time. There is no suggestion, however, that such phenomenon could be utilized to achieve a hydrodynamic balance for a tablet such that it will remain floating on the gastric fluid in the stomach for an e~tended period of time as in the subject invention.

In accordance with the present invention, formulations for the preparation of solid sustained release dosage forms for oral administration are provided which are hydrodynamically balanced to have a bulk density (specific gravity) of less than one in contact with gastric fluid and which therefore will remain floating in gastric fluid which has a specific gravity of between 1.004 and 1.010. The sustained release formulations of the present invention comprise a homogeneous mixture of one or more medicaments with one or more hydrophilic hydro-colloids which, in contact with gastric fluid at body tempera-ture, will form a soft gelatinous mass on the surface of saidmixture, thus causing it to enlarge somenhat and to acqui~e a bulk density (specific gravity) of less than one. The medica-ment is slowly released from the surface of the gelatinous mass which, due to its buoyancy, remains buoyant in the gastric fluid. Ultimately, after substantially all of the medicaments therein are released, the gelatinous mass disperses. The sustained release formulation of this invention is orally ... . ..
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335~3 administered in the form of tablets or capsules, e~g , hard or soft gelatin capsules.

Upon oral ingestion of solid pharmaceutical dosage forms prepared from the formulations of the present invention, the capsule shell or the tablet film coating, if such is present, dissolved leaving the contents in contact with gastric fluid.
Upon contact with ~astric fluid, the outermost hydrophilic colloid hydrates to form an outside barrier which substantially retains the shape of the capsule or tablet and therefore acts to prevent the mass from disintegrating. The hydrated layer thereafter slowly dissolved releasing medicament. There is also a release of medicament by leaching action of or near the surface of the mass. As new surface is exposed to gastric fluid it becomes hydrated, thus maintaining the integrity of the barrier. This process is continuously repeated until the medicament is substantially leached out. Thereafter the remaining matrix which is still buoyant in gastric fluid slowly dissolves and is eliminated.

It has been found that the release pattern and resulting blood levels attained with the sustained release formulation .;
of the invention has advantages over other sustained release mechanisms known in the art, particularly wherein the medica r ment contained therein is principally absorbed and/or exerts S~sf~ L
~_J its therapeutic activity in the stomach or duodenum~=~
release formulations prepared in accordance with the present invention unexpectedly produce optimum blood levels with . ~,,; .,. 1, .
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:10~3358 certain medicaments, e.g., chlordiazepoxide. ~he results with chlordiaæepox-ide were superior to known sustained release formulation previously tried, each of which had failed to produce satisfactory blood levels. In addition, the sustained release formulation of the present invention ~mexpectedly pro-vides an excellent means for administering antacid substances over a prolong-ed period of time.
In order to successfully practice the present invention, the hydro-colloids utilized must hydrate in acidic medium, e.g., gastric fluid with a pH equivalent to 0.1~ hydrochloric acid, :. - ... . . .

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n6'f e/y i.e., a pH of i~UK~Y~4~1.2. Furtermore, although the initial bulk density of the formulation of the invention may initially be greater than one, it is essential that the formu-lation be hydrodynamically balanced to have a bulk density of less than one when in contact with gastric fluids to assure buoyancy. There are a number of methods whereby the rate of release of medication from the sustained release formulation of the present invention can be adjusted. First, the choice of a particular hydrocolloid or mixture of hydrocolloids can affect the release rate, e.g., high viscosity hydrocolloids, e.g., methylcellulose 60 HG, 4000 cps, hydrate more slowly and maintain a soft mass for a longer time than low viscosity hydrocolloids, e.g., methylcellulose 60 HG, 10 cps. Further, edible, pharmaceutically inert, fatty materials having a specific gravity of less than one can be added to the formula-tion to decrease the hydrophilic property of the formulation and therefore increase buoyancy. Examples of such materials include: a purified grade of beeswax; fatty acids; long chain fatty alcohols such as, for example, cetyl alcohol, myxistyl alcohol, stearyl alcohol, glycerides such as glyceryl esters of fatty acids or hydrogenated aliphatic acids such asl for example, glyceryl monostearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil and the like; oils such as mineral oil and the like.

There may also be incorporated into the sustained release formulations of the present invention additional edible non-toxic ingredients recognized in the art of pharmaceutical ; , . , ~ ,~ .

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compounding such as excipients, preservatives, stahilizexs, table~ting lubri-cants and the like. The choice o~ such matarials and the amounts to be util-ized are considered to be within the purview of one skilled in the art. It is to be borne in mind, however, that such conventional pharmaceutical adjuncts which might adversely affect the hydrodynamic balance of the sustained release formulation of the present invention are not suitable for use therein.
The a unt of the active medicament or mixtures thereof in the sus-tained release for~ulation of the present invention can vary over a wide range, i.e., from about 0.1% by weight to about 90~ by weight. ~he a~oun~ of active substances present is usually between about 5% by weight and 50~ by weight. Factors which govern the amount of active substance present in the sustained release for~ulations of the present invention are, for example, the a~ount required to yive full therapeutic dosage, the bulk density thereof, the hydrophilic or hydrophobic properties thereof, the stability thereof and the like. These proper~ies are known or are easily ascertainable by a person skilled in the art and the formulation adjustments required to incorporate any given therapeutically active substance into a sustained release formula-tion in accordance with the present invention are considered to be within the purview of the art. The am.ount of the hydrocolloid ~' .

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1~733S~3 ingredient to be utilized will vary in relation to the amounts and properties of the active ingredient and inert pharmaceutical adjuncts utilized.
Wherein one or a mixture of fatty materials in present in the SU5-tained release formulations of the invention, such material comprises up to about 60% by weight of the total formulation. In general, wherein the formu~
lations do contain a fatty material, such material is present in from about 5% by weight to about 30~ by weight. ~he amount of fatty material utilized is governed by the amounts and physical characteristics of both the active ingredient and the hydrocolloid with the object being to achieve a hydro-dynamically balanced formulation, i.e., a formulation which acquires a bulk density (specific gravity) of less than one in gastric fluids.
The amount of edible, inert pharmaceutical adjunct materials whichmay be present in the sustained release formulations of the present invention will also vary in accordance with the amounts and physical properties of ~he other ingredients. Such materials which themselves have a bulk density of less than one will enhance the buoyancy of the formulation. ~ore importantly, it is possible to utilize the selection of inert pharmaceutical adjunct materials to , ,:

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~733~8 modify the rate of release of the formulati~n. For example, soluble excipients, e.g., lactose, mannitol and the like, will increase the rate of release whereas insoluble excipients e.g., dicalcium phosphate, terra alba and the like, will decrease solubility. Wherein such pharmaceutical adjunct material are included in the formulations of the invention, they can be present in up to 80~ by weight of the final Eormulation.
Generally, such conventional pharmaceutical adjuncts are present in from about 5% by weight to about 60% by weight of the formulation. The inclusion of and choice of such materials is again considered to be within the purview of the art utilizing the principles of the present invention.

7~ re/ease V The hydrodynamically balanced sustained ~C~2 dosage formulations of the present invention are prepared by techniques well established in the art. Wherein the formu-lations of the invention are to be administered in the form of capsules, all that is required is the thorough mixing of all ingredients and milling or comminuting to form a homogeneous mixture of relatively fine particle size.
Occasionally, however, the conventional pharmaceutical techniques of slugging, wet granulating or extruding may be required to achieve proper fill weight in the capsule. The resulting mixture is then filled into suitable pharmaceutical carsules with hard gelatin capsules being preferred. The capsule should be completely filled. Adjustments in the formulation ,, .~ . . .
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1~335~3 necessary to achieve this end are within the skill of the art.

Wherein the formulations of the present invention are ~ 5~er~
ad~i-ne&ter-c~ in the form o~ tablets, such tablets are prepared by conventional techniques. In most instances it is necessary to utilize the technique of wet granulation followed by compression into tablets. However, where the physical properties of the ingredients will permit, tablets may be prepared by direct compression of a homogeneous mixture of the ingredients. Such tablets contain conventional tabletting lubricants and may also contain other pharmaceutical adjunct materials in accordance with the criteria set forth herein.
It is to be noted that many of the hydrocolloids utilized in the practice of the invention are conventionally used in pharmaceutical compounding as tablet binders and as such, are incorporated into the tablet formulation in the form of a solution or dispersion in a suitable solvent.

In the practice of the invention, however, the hydro-colloid ingredient is incorporated into the formulation in dry form, thus excluding it from wet granulation techniques where they are utilized. However, a small percentage o~ the hydro-colloid ingredient may be utilized in accordance with convention techniques as a tablet binder. Wherein a hydro-colloid such as described herein is utilized conventionally as a tablet binder and is combined into the formulation in . .

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~33S~3 the presence of a solvent, such hydrocolloid does not function to facilitate the buoyancy of the tablets prepared therefrom.

Tablets prepared in accordance with the present invention can be manufactured on conventional tabletting equipment. However, it is critical that they are not compressed to a degree of hardness such that they will not acquire a bulk ~ of less than one in contact with gastric fluids. In accordance with the present invention, tablets which initially have a density greater than one will be buoyant in gastric fluids. This buoyancy results from a combination of an increase in the bulk volume of the tablet when it contacts gastric fluids due to the hydration and swelling of the hydrocolloid particles on the tablet surface and the internal voids in the tablet center remaining dry due to the barrier formed by the hydrocolloid particles. Therefore, it is critical that the tablets are not compressed to a degree of hardness such that the porosity is materially reduced and the hydrocolloid particles on the tablet surface are compacted so tightly that rapid hydration is retarded. It will be appreciated that the maximum hardness to which a tablet having an initial density greater -than one can be compressed will vary both with the initial density of the tablet and the size of the tablet~ The hardness for any tablet will lie between the maximum at which a buoyant tablet can be produced in accordance with the teachings herein and a minimum re~uired :. , , ~ .:.::
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for tablets to meet basic pharmaceutical tests of stability during shipment, and the like. This range of hardness can be easily determined ~y standard pharmaceutical hardness measurements combined with te!3ting of the buoyancy of samples of tablets di~ferent hardness in gastric fluid. Such determinations are considered to be within the skill of the skilled artisan.

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3:~58 It is reported in the lit0rature that the irritation of the stomach caused by aspirin is the resul~ of contact of this very acidic substance with the stomach walls. m erefore, it will be appreciated that the formulations of the invention axe particularly advantageous for the administratlon of aspirin since they remain buoyant in gastric fluid.
Medicaments co which the sustained release formulation of the sub-ject invention is particularly amenable are chlordiazepoxide and diazepam.
It is noteworthy that, after a number o~ sustained release mechanisms known to the art proved unsuccessful, superior results were obtained with chlordiaz-epoxide utilizing the formulations of the subject invention. For the ben~o-diazepines the formulation according to the present invention is preferably brought in the form of a capsule.
The sustained release ~ormulations of the present invention are also particularly amenable to the administration of ~ 16 -. ~
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~L~;173358 antacids such as the oxides, hydroxides and carbonates of magnesium aluminu~
hydroxide, magnesium txisilicate and the like. Whexein such substances gener-ate carbon dioxide, bubbles will become entrapped by the hydrated outer layer thus enhancing the buoyancy of the formulation. Amo~mts of carbon dioxide generating bases can also be utilizad in non-antacid formulations to enhance buoyancy. It is further within the scope of the present invention to adminis-ter the formulations hydrodyn~mically balanced in accordance with the inven- r tion as one layer of a two layer tablet. The remaining layer contains medica-ment in a conventional formulation free of sus~ained release ingredients.
m is unique tablet, upon ingestion, provides an immediate release of medica-mant and a buoyant layer which continues to release medicament o~er a period of time while being retained in the stomach. Such unique two-layered tablets are particularly advantageous for the administration of antacid substances.
me sustained release formulation of the present invention has been found to remain buoyant in gastric fluid despite the presence of surfactants or food. me efficacy of madicaments administered utilizing ~he sustained release formulation of the presen~ invention has been found to be independent of the site of absorption of the particular medicament. Utilizing dogs which had ingested capsules containing barium sulfate in the formulation in accord-ance ,l ,j, , .

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with the present invention, it has been demonstrated by the use of x-ray techniques that the formulati.on remains buoyant in the gastric fluid and does not adhere t:o the walls of the stomach.

The following examples illustrate the invention.

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Example l Sustained release capsules containing chlordiazepoxide were prepared as follows:

Ingredient mg/ca~sule Chlordiazepoxide 30.6 Hydroxypropylmethylcellulose, 4000 cps 100.4 Lactose Anhydrous 30.0 .1 '~ ` Sterotex K* 58.0 Talc 50 0 Magnesium Stearate Total 275.0 *A hydrogenated cottonseed oil manufactured by Capital City Products, Colubus, Ohio.

~-~ The chloridazepoxide, methylcellulose and lactose were ~ f',l e~
homogeneously blended in a suitable blender a~er which the mixture was passed through a Comminuting Machine at high speed utilizing a No. 2B screen with knives forward. The Sterotex K, talc and magnesium stearate were then added to the mixture and the whole blended for an additional five minutes. The mixture was then passed through a Comminuting Machine at high speed utilizinga No. O plate, knives forward. The blending and milling procedures were repeated and the mixture was filled into No. 2 size pink opaque capsules.

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The thus-formed capsules were tested for in vitro release rates by the rotating bottle technique in simulated gastric fluid. The results of these tests are set forth in Table I.

TABLE I
Percent of Active Ingredient Released Time (hours) Gastric Fluid (pH 1.2) O O

3.5 86 Accelerated chemical stability tests at 55C., in a light chamber and at 37 C./85~i R.H., both-in amber and polyethylene bottles with a silica plug showed the capsules to have acceptable stability.

Samples of the above capsules were tested in vivo in man in comparison with three commercial capsules each containing 10 mg. chloridazepoxide administered at 0, 4 and 8 hours. The results are set forht in Table II.

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335~3 It is eYident from the abo~e data that the sustained release capsules ~atch very well with the regimen of single dose capsules.

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Sustained release antacid capsules were prepared asfollows:

Ingredient m~/capsule FMA-ll* 254.7 Magnesium Oxide, Light 127.0 Lactose, hydrous 20.3 Hydroxypropylmethylcellulose, 4000 cps 63.0 Gum Karaya, Stein Hall 31.0 Talc, tablet grade 24.0 Magnesium Stearate 5.0 Total 525.0 *Aluminum Hydroxide-Magnesium carbonate co-precipitate - Reheis Co., Berkley Heights, New Jersey.

lL 15 The FMA-11, light magnesium oxide, lactose and magnesium stearate were blended in a suitable mixer for 10 minutes and then passed through a Comminuting Maching using a No. 1 plate at medium speed, knives forward. The mixture was then slugged on a suitable press using 3/4" F.F.
punch and the slugs milled on a Comminuting Machine at medium speed using a No. 1 plate, knive forward. The resulting granules were thoroughly mixed with the remaining ingredients and filled into No. O capsules utilizing conventional capsule ~r~JemA~K

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,51.. ~i filling equipment.

As the Federal Register does not give a specific method for testing a sustained release antacid preparation, the capsules were tested by the following method. A capsule is placed in 300 ml. of O.lN hydrochloric acid in a stoppered flask rotated at 40 rpm. A 50 ml. sample is withdrawn at a specified time and titrated with O.lN NaOH to pH 3.5 which is the neutralization point given in the Federal Register for acid neutralizing capacity. The amount of acid consumed was calculated from the sample. The results are given in Table IV. The capsules remained floating throughout the test.

TABLE IV

T _ Antacid Release 1st hour 42.1%
2nd hour 96.7%
3rd hour 104%

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Exam~le ~

Sustained release aspirin capsules were prepared as follows:

Ingredient _~./ca~sule Acetylsalicyclic Acid, Micronized 400 Dicalcium Phosphate, anhydrous 20 Hydroxypropylcellulose 40 Tragacanth 100 Total 560 All ingredients except tragacanth were thoroughly mixed and passed through a Comminuting Machine using a No. 00 plate, knives forward. The mixture was granulated with anhydrous ethanol, dried and milled. The tragacanth was then blended with the mixture and the whole filled into No. 0 capsules.
The capsules were found to remain buoyant in the gastric fluid.

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Sustained release aspirin tablets containing 7.5 grains aspir~n were prepared from the following granulations:

Granulation A Mg.
Acetylsalicyclic Acid 500 Hydroxypropylmethylcellulose, 400 cps 125 Hydroxypropylmethylcellulose, 15 cps 3 Total 628 Granulation B
Calcium Carbonate, precipitated 65 Magnesium Carbonate 20 Mannitol 10 Carboxymethylcellulose 2 Total 97 The two granulations were homogeneously mixed with

5 mg. talc and compressed using capsule-shaped punches to a hardness of 5 to 6 S.C.U. Hardness should not exceed 11 S.C.U.
for tablet to remain buoyant.

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Sustained release two-layered antacid tablets were prepared as follows:

Layer A-Immediate Release In~redient ms/tablet FMA-ll* 160.0 Methylcellulose 5.8 Magnesium Oxld~ 80.0 Primojel** 10.0 Magnesium Stearate 2.5 Total 258.3 * Aluminum hydroxide-magnesium carbonate co-precipitate -Reheis Co.
** Sodium carboxymethyl starch - E. Mendel & Co.; Carmel, New York The FMA-ll and magnesium oxide were mixed in a suitable mixer. The resulting mixture was granulated utilizing a 2.5%
by weight solution of the methylcellulose in a mixture of equal parts water and ethyl alcohol. The granulation was dried overnight at 60C. The dried granulation was then milled, combined with the Primojel and magnesium stearate and mixed for five minutes. The resulting homogeneous mixture was then compre~sed on a conventional two-layer tablet press.

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Layer B-Sustained Release Ingredient mg/tahlet ; ) FMA-ll 170 Magnesium Oxide 85 Methylcellulose 4000 cps (dry) 90 Methylcellulose 4000 cps (wet) 6 Ethylcellulose 90 Direct Compression Grade Starch 35 Syloid* 30 Magnesium Stearate 23 Total 529 *Purified silicon dioxide - W. R. Grace & Co., Baltimore, Maryland ~mA
The ~-11 and the magnesium oxide were mixed in a suitable mixer. The resulting mixture was granulated with a solution of the methylcellulose (wet) in a mixture of equal parts water and ethyl alcohol and the granulation dried overnight at 60C. The resulting granulation was combined with the methylcellulose (dry), ethylcellulose, direct compression grade starch and Syloid and thoroughly mixed for about 10 minutes. The magnesium stearate was added and the mixture mixed for an additional five minutes. This mixture was then compressed on a conventional two-layer tabletting machine with Layer A to a standard concave capsule shape 3/4"x5/16". The acceptable hardness of the tablets was between ~ rr~Jem~K

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12 and 14 s.c.u. and it was found that the hardness could not exceed 16 s.c.u.

A sample of the two-layer antacid tablets thus formed was placed in a beaker containing gastric fluid and equipped with a magnetic stirrer running at slow speedO It was observed that the immediate release layer separated and sank to the bottom of the beaker in fine particulate form. The sustained release layer remained floating for two hours slowly releasing medication.

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Claims (4)

1, A sustained release pharmaceutical formulation containing as the active ingredient a benzodiazepine selected from the group consisting of chlordiazepoxide and diazepam, one or more antacid compounds or acetylsalicylic acid, said formulation being hydrodynamically balanced so that, upon contact with gastric fluid, said formulation acquires and maintains a bulk density of less than 1 thereby being buoyant in said fluid and remaining buoyant in the gastric fluid of the stomach until substantially all of the active ingredient contained therein has been released, said for-mulation comprising a homogeneous mixture of said active ingredient; from 0 % to 80 % by weight of therapeutically inert, pharmaceutically acceptable adjunct materials;
from 0 % to 60 % by weight of a fatty material having a specific gravity of less than 1 and from 20 % by weight to 75 % by weight of one or a mixture of hydrocolloids selected from the group consisting of methyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose and sodium-carboxymethylcellulose to provide upon contact with gastric fluid, a water-im-permeable barrier on the surface of said formulation.

2. A sustained release formulation according to claim 1, which is a capsule containing as the active ingredient a benzodiazepine selected from the group consisting of chlordiazepoxide and diazepam, said capsule comprising a finely particulate homogeneous mixture of said benzodiaze-pine; from 5 % by weight to 60 % by weight of said adjunct materials; from 0 % to 60 % by weight of said fatty material and from 20 % by weight to 75 % by weight of one or a mix-ture of said hydrocolloids.

3. A sustained release formulation according to claim 1, consisting of a two-layered tablet comprising:
a first layer containing one or more antacid substances and therapeutically inert pharmaceutically acceptable adjunct materials free of sustained release ingredients;
and a second layer containing as the active ingredient , one or more antacid compounds, said tablet being hydro-dynamically balanced so that, upon contact with gastric fluid, said second layer acquires and maintains a bulk density of less than one thereby being buoyant in said fluid and remaining buoyant in the gastric fluid of the stomach until substantially all of the antacid compounds contained therein have been released therefrom, said second layer comprising a homogeneous mixture of said antacid compounds, from 0 % to 80 % by weight of said adjunct materials, and from 20 % by weight to 75 by weight of one or a mixture of said hydrocolloids to provide, upon contact with gastric fluid, a water im-permeable barrier on the surface of said second layer, said tablet being compressed to a hardness of from 12 to 14 S.C.U.

4. A sustained release formulation according to claim 1, which is a tablet containing as the active ingredient acetylsalicylic acid, said tablet comprising a homogeneous mixture of acetylsalicyclic acid; 0 % to 80 % by weight of said adjunct materials and from 20 % by weight to 75 % by weight of one or a mixture of said hydrocolloids, said tablet being compressed to a hardness of from 5 to 6 S.C.U.