IE43083B1 - Substained-release formulations - Google Patents

Abstract

Solid pharmaceutical formulations are described which have a sustained release effect and which are buoyant in gastric juice. The formulation is present in the form of a homogeneous mixture. This mixture contains at least one therapeutic active compound, up to 80% by weight of therapeutically inert, pharmaceutically acceptable auxiliary substances, up to 60% by weight of a fatty material having a specific weight less than 1 and such a proportion of a hydrocolloid or of a mixture of hydrocolloids, incorporated into the formulation essentially in the dry form, that, after contact with the gastric juice, a layer which is impermeable to water is generated on the surface of this homogeneous mixture.

Description

The present invention relates to sustained-release pharmaceutical formulations and processes for their manufacture.

According to the present invention there is provided a sustained-release pharmaceutical formulation in solid dosage form for or‘al administration, which formulation comprises a homogeneous mixture for one or more medicaments, 0 to 80% by weight of one or more therapeutically inert, pharmaceutically acceptable adjunct materials, 0 to 60% by weight of one or more edible fatty materials having a specific gravity of less than 1 and one or more hydrocolloids which hydrate in an acid medium, at least part of the hydrocolloid or hydrocolloids being incorporated in a mixture by combining said hydrocolloid (s) in dry, particulate form with another ingredient or mixture of ingredients in a dry and essentially non-liquid state whereby the hydrocolloid(s) so incorporated retains said dry, particulate form, and any subsequent treatment being in a dry and essentially non-liquid state whereby the solid dosage form is prepared from a homogeneous mixture containing the hydrocolloid(s) so incorporated in dry, particulate form so that when the mixture is in contact with gastric fluid the iydrocolloid(s) so incorporated forms by hydration a water impermeable barrier, which barrier by sequential erosion thereof by the gastric fluid and reformation as fresh hydrocolloid(s) so incorporated is exposed allows slow release of medicament, ;he proportion of hydrocolloid(s) so incorporated and the other .ngredients being chosen whereby the said hydrocolloid(s) ipon hydration in gastric fluid provides a solid dosage form rhich floats in gastric fluid.

The sustained-release pharmaceutical formulation in ccordance with the invention may be manufactured by a process omprising forming a dry, essentially non-liquid homogeneous ixture by mixing together said medicament(s), hydrocolloid(s) n dry, particulate form, and any said adjunct(s) and/or said dible fatty material(s) and bringing the mixture directly into solid dosage farm. Said medicament(s) and hydrocolloid(s) may a blended together first and said adjunct(s) and/or edible itty material(s) added to the blend.

Alternatively, the formulation may be manufactured by a rocess comprising blending together said medicament(s), adjunct(s) ld/or edible fatty material(s) to form a dry, essentially non.quid blend, mixing said hydrocolloid(s) in dry particulate >rm with the blend, effecting any further process steps in a y, essentially non-liquid state, and bringing the resulting xture into a solid dosage form. - 2 Γ* The convenience of administering a single dose of medication which releases an active medicament over an extended period of time as opposed to the administration of a number of single doses at regular intervals has long been recognised in 5 the pharmaceutical field. The advantage to the patient and clinician in having consistent and uniform blood levels of medication over an extended period of time are likewise recognised. In most sustained-release preparations known in the pharmaceutical field, medicinal agents are either coated with varying thicknesses of some type of relatively insoluble material or are imbedded in a rigid lattice of resinous material. In such preparations, the object is to continuously provide medicament 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 formulation briefly outlined earlier can be disadvantageous in that certain classes of active medicaments are not suited to absorption during passage through the gastrointestinal tract 2o due to their physiochemical properties and/or favourable 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) 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 foregoing 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 invention.

The principle of sustained-release which characterises the pharmaceutical formulation of the present invention is unique, that is to say,, the formulation remains 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 recognised in the field and the concept of a floating formulation is recognised, there is no teaching which recognises the application of buoyancy to sustained-release as in the present invention.

For example, United States Patent No 3 418 999 (Davis) teaches a tablet which is buoyant. However, the buoyancy of the tablet is disclosed as being merely an adjunct to swallowing - 4 43083 and there is no suggestion therein of applying the buoyancy to sustained-release. The Davis tablets also must have an initial density of less than 1 gm/cc, whereas tablets of the present invention need not.

The concept of a tablet which swells when in contact with gastric fluid is also recognised in the field. For example. United States Patent No 3 574 820 (Johnson et al) teaches 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 recognised in the field. United States Patent No 3 147 187 (Playfair) teaches theincorporation of a swelling gum or proteinaceous material into a sustained-release tablet to aid in the distintegration 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 particulate form as in the present invention whereby it functions to facilitate the buoyancy of the tablet.

Finally, United States Patent No. 3,065,143 (Christenson et al) teaches the use of a hydrocolloid in a sustainedrelease 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 used to achieve a specific gravity for a tablet such that it will remain floating on the gastric fluid in the stomach for an extended period of time as in the present invention.

In accordance with the present invention, there are provided formulations which in contact with gastric fluid have a specific gravity of less than 1 and which therefore will remain floating in gastric fluid whcih 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 hydrophillic hydrocolloids which,in contact with gastric fluid at body temperature, will form a soft gelatinous mass on the surface of said mixture, thus causing it to enlarge somewhat and to aquire a specific gravity of less than one.

The medicament 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 have been released, the gelatinous ; mass disperess. The sustained-release formulation of this invention is orally administered in the form of, for example, tablets or capsules (e.g. hard or soft gelatin capsules). - 6 43083 Upon oral ingestion of such solid pharmaceutical dosage forms, the capsule shell or the tablet film coating, if such is present, dissolves leaving the contents in contact with gastric fluid. Upon contact with gastric fluid, the outermost hydrophilic colloid hydrates to form an outside barrier which acts to prevent the mass from disintegrating. The hydrated layer thereafter slowly dissolves releasing the 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 present invention has advantages over other known sustained-release mechanisms, particularly those in which the medicament contained therein is principally absorbed and/or exerts its therapeutic activity in the stomach or duodenum. Sustained-release formulations in accordance with the present invention unexpectedly produce optimum blood levels with certain medicaments (e.g. chlordiazepoxide). The results with chloridazepoxide were superior to known sustained-release formulations previously tried, each of which had failed to produce satisfactory blood levels. In addition, the sustained release-formulation of the present invention unexpectedly provides an excellent means for administering antacid substances over a prolonged period of time.

.Hydrocolloids suitable for use in the sustained-release formulations of the present invention include one or more natural, partially* or totally synthetic anionic or, preferably, nonionic hydrophilic gums, modified cellulosic substances or proteinaceous substances such as, for example, acacia, gum tragacanth, locust bean gum, guar gum, karaya gum, agar, pectin, carrageen, soluble and insoluble alginates, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodiumcarboxymethylcellulose, carboxypolymethylene (Carbopol -? Registered Trade Mark - Cabot Corporation), gelatin, casein, zein, bentonite, Veegum (R. T. Vanderbilt Co.). A preferred hydrocolloid is hydroxypropylmethylcellulose. The use of such materials in pharmaceutical compounding is recognised in the field. For example, United States Patent No. 3 555 151 (Kaplan et al) discloses the use of such hydrocolloids in sustained-release antacid preparations.

In order to be useful in the present invention, the hydrocolloids used must hydrate in acidic medium (e.g. gastric) fluid with a pH. equivalent to 0.1-N hydrochloric.acid, i.e. a pH of approximately 1.2). Furthermore, although the initial bulk density of the formulation of the invention may initially be greater than one gm/cc, it is essential that the formulation should have a specific gravity of less than 1 when in contact with gastric fluids to assure buoyancy. There are a number of methods whereby the rate of release of medicament 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; for example, high viscosity hydrocolloids such as methylcellulose 60 HG, 4000 cps, hydrate more slowly and maintain a soft mass for a longer time than low viscosity hydrocolloids such as methylcellulose 60 HG, 10 cps. Further, edible and pharmaceutically inert fatty materials having a specific gravity of less than one can be added to the formulation to decrease the hydrophilic property of the formulation and therefore increase buoyancy. Examples of such materials include purified grade of beeswax, fatty acids, long-chain fatty alcohols such as, for example, cetyl alcohol, myristyl alcohol and stearyl alcohol, glycerides such as glyceryl esters of fatty acids or hydrogenated aliphatic acids such as, for example, glyceryl monostearate, glyceryl distearate,and glyceryl esters of hydrogenated castor oil , oils such as mineral oil.

There may also be incorporated into the sustained-release formulations of the present invention additional edible non-toxic ingredients recognised in pharmaceutical compounding such as excipients, preservatives, stabilisers and tabletting lubricants. The choice of such materials and the amounts thereof used will be readily apparent. It should be borne in mind, however, that such conventional pharmaceutical adjuncts which might adversely affect the ability of the sustained-release formulation of the present Invention to float when in contact with gastric fluid are not suitable for use.

The amount of the active medicament or mixtures thereof in the sustained-release formulation of the present invention can vary over a wide range (e.g. from about 0.1% by weight to about 90S by weight). The amount of active medicaments present is usually between 5% by weight and 506 by weight. Factors which govern the amount of active medicament present in the sustained-release formulations of the present invention are, for example, the amount required to give full therapeutic dosage, the bulk density thereof, the hydrophilic or hydrophobic properties thereof, the stability thereof and the like. These properties are known or are easily ascertainable and the formulation adjustments required to incorporate any given therapeutically active medicament into a sustained-release formulation in accordance with the present invention will also be readily apparent. The amount of the hydrocdlloid ingredient present in the sustained-release formulation of the present invention may also vary within a wide range (e.g. from 5% by weight to 99.96 by weight). Again, the amount of hydrocolloid ingredient to be used will vary in relation to the amounts and properties of the active medicament and inert pharmaceutical adjuncts used. Generally, the amount of hydrocolloid present will be from between about 20% by weight to about 75% by weight.

When a fatty material or a mixture of fatty materials is present in the sustained-release formulations of this invention, such material comprises up to 60% by weight of the total formulation. In general, when the formulations do contain a fatty material, such material is present in an amount of from 56 by weight.to 30% by weight. The amount of fatty material present is governed by the amounts and physical characteristics of both the active medicament and the hydro10 4 3 0 8 3 colloid with the object being to achieve a formulation which acquires a specific gravity of less, than 1 in gastric fluids.

The amount of edible inert pharmaceutical adjunct materials which may be present in the sustained-release formulations of the present invention will also vary according to the amounts and physical properties of the other ingredients. Such materials, which themselves have a bulk density of less than 1 gm/cc, will enhance the buoyancy of the formulation. More importantly, it is possible to use the selection of inert pharmaceutical adjunct materials to modify the rate of release of the formulation. For example, soluble excipients (e.g. lactose and mannitol) will increase the rate of release, whereas insoluble excipients (e.g. dicalcium phosphate, and terra alba) will decrease solubility. When such pharmaceutical adjunct material are included in the formulations of this invention, they can be present in up to 80S by weight of the final formulation. Generally, such conventional pharmaceutical adjuncts are present in an amount of from 5% by weight to 80S by weight of the formulation. The reasons for inclusion of and choice of such materials will be readily apparent.

The sustained-release dosage formulations of the present invention are manufactured by well-established techniques. When the formulations 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 4308 3 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, and these may be used subject to the limitations discussed above, that is to say provided the dry, particulate form of at least part of said hydrocolloid(s) is retained. The resulting mixture is then filled into suitable pharmaceutical capsules, with hard gelatin capsules being preferred. The capsule should be completely filled. Adjustments in the formulation necessary to achieve this end will be readily apparent.

When the formulations of the present invention are administered in the form of tablets, such tablets > are prepared by conventional techniques, but again subject to the above-mentioned limitations. In most instances, it is necessary to use the technique of wet granulation for some of the ingredients followed by addition of. at least part of the hydrocolloid(s) in dry, particulate form to the dried granulated ingredients, and compression into tablets. However, where the physical properties of the ingredients will permit, tablets may be prepared by direct compression of a dry homogeneous mixture of the ingredients. Such tablets contain conventional tabletting lubricants and may also contain other pharmaceutical adjunct materials λ» 12 43083 in accordance with the criteria set forth herein. It will be appreciated that many of the hydrocolloids used in this 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 present invention, however, the effective part of the hydrocolloid ingredient is incorporated into the formulation in dry form, thus excluding it from wet granulation techniques where such are used. However, part, usually a small percentage, of the hydrocolloid ingredients may be used in accordance with conventional techniques 13083 as a tablet binder. When a hydrocolloid of the kind described herein is used conventionally as a tablet binder and is combined into the formulation in 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 specific gravity less than 1 in contact with gastric fluids. In accordance with the present invention, tablets which initially have a density greater than 1 gia/cc will be buoyant in gastric fluids. This buoyancy results from a combination of an increase in the bulk volume of the tablet when it comes into contact with gastric fluids due to the hydration and swelling of the hydrocolloid particles on the tablet surface and the internal voids in the tablet centre 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 1 gm/cc 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 present invention and a minimum required for tablets to meet basic pharmaceutical tests of stability during shipment and the like. - 14 43083 This range of hardness can be easily determined by standard pharmaceutical hardness measurements combined with testing of the buoyancy of samples of tablets of different hardness in gastric fluid. Such determinations will be readily apparent.

The medicament or combination of medicaments which are amenable to inclusion in the sustained-release formulations of the present invention include any medicament suitable for oral administration where sustained-release therapy is medically advisable. It will be appreciated that the present invention is not limited to any particular medicament or class of medicaments. Further, the sustained-release formulation of the present invention is not restricted to medicaments which are principally absorbed from the stomach since it has been found that it is equally efficacious with medicaments which are absorbed from the intestines (e.g. chlorpheniramine maleate). The sustained-release formulation of the present invention can, of course, not be used with medicaments which are acid-sensitive. Among the various classes of medicaments which are advantageously administered via a sustained-release dosage form are, for example, antibiotics (e.g. penicillins, cephalosporins and tetracyclines), catecholamines (e.g. epinephrine and the amphetamines), analgesics (e.g. aspirin), sedatives (e.g. barbiturates), anticonvulsants, antinauseants, muscle relaxants, hypotensives, and vitamins. It is reported in the literature that the irritation of the stomach caused by aspirin is the result of contact of this very acidic substance with the stomach walls. Therefore, it will be appreciated that the present formulations are particularly advantageous for the administration of aspirin since they remain buoyant in gastric fluid.

A class of medicaments to which the sustained-release formulation of the present invention is particularly amenable comprises the benzodiazepines (e.g. chlordiazepoxide, diazepam, oxazepam and bromazepam). It is noteworthy that, after a number of known sustained-release mechanisms have proved to be unsuccessful, superior results have been obtained with the present formulations containing chlordiazepoxide.

For the benzodiazepines, the present formulation is preferably brought into the form of a capsule.

The sustained-release formulations of the present invention are also particularly amenable to the administration of medicaments which are only absorbed through the stomach or upper portion of the intestines (e.g. ferrous salts such as ferrous fumarate) or which exert a therapeutic effect in the stomach (e.g. antacids such as the oxides, hydroxides and carbonates of magnesium, aluminium hydroxide and magnesium trisilicate). When such substances generate carbon dioxide, bubbles will become entrapped by the hydrated outer layer and will thus enhance the buoyancy of the formulation. Amounts of carbon dioxide-generating bases can also be used in non-antacid formulations to enhance buoyancy.

It is also within the scope of the present invention to provide formulations which are sustained-release in one layer of a two layer tablet. The remaining layer contains medicament in a conventional formulation free from sustained-release ingredients. This unique tablet, upon ingestion, provides an immediate release of medicament and a buoyant layer which continues to release medicament over a period of time while being retained in the stomach. Such unique two-layered - 16 43083 tablets are particularly advantageous for the administration of antacid substances.

The sustained-release formulation of the present invention has been found to remain buoyant in gastric fluid despite the presence of surfactants or food. The efficacy of medicaments administered using the sustained-release formulation of the present invention has been found to be independent of the site of absorption of the particular medicament. Using dogs which had ingested capsules containing barium sulphate in the formulation in accordance with the present invention, it has been demonstrated by the use of x-ray techniques that the formulation remains buoyant in the gastric fluid and does not adhere to the walls of the stomaeh. - 17 43083 The following Examples illustrate the present'invention: ' Example 1 Sustained-release capsules containing the following Ingredients were prepared: Ingredient mg/capsule Chlordiazepoxide 30.6 Hydroxypropylmethylcellulose, 4000 cps 100.4 Lactose, anhydrous 30.0 Sterotex K* 58.0 Talc 50.0 Magnesium stearate 6.0 Total 275.0 *A hydrogenated cottonseed oil manufactured by Capital City Products, Columbus, Ohio.

The chlordiazepoxide, methylcellulose and lactose were homogeneously blended in a suitable blender, after which the mixture was passed through a comminuting machine at high speed using a No. 2B screen with knives forward. The Sterotex K, talc and magnesium stearate were then added to the mixture and the whole was blended for an additional 5 minutes. The mixture was then passed through a comminuting machine at high speed using a No. 0 plate with knives forward. The blending and milling procedures were repeated and the mixture was filled into No. 2 size pink opaque capsules.

The thus-formed capsules were tested for in vitro release rates by the rotating bottle technique in simulated - 18 43083 gastric fluid. The results of these tests are set forth in Table I.

TABLE I Percentage of Active Medicament Released Time (hours) Gastric fluid (pH 1.2) 0 0 1 39 2 61 3.5 86 10 5 ; 94 7 100 Accelerated chemical stability tests at 55°C in a light chamber and at 37°C/85% R.H., both in amber and polyethylene bottles with a silica plug, showed the capsules to have acceptable stability.

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

TABLE II Capsule type Time of Plasma level Maxima (hours) Plasma Level Maxima (gamma/ml) Total area under Plasma Level Curve Sustained-Release Capsule 30 mg Mean 9.6 1.06 27.2 Range (4-15) (0.64-^1.87) (20.2-34.0) No. of subjects 6 6 6 Commercial 10 mg Capsules at 0.4 and 8 hours Mean 9.4 1.04 24.5 Range (5.5-15) (0.64-1.73) (10.1-60.6) No. of subjects 17 17 17 It is evident from the foregoing data that the sustained-release capsules match very well with the regimen of single dose capsules.

Example 2 Antianaemic sustained-release capsules containing the following ingredients were prepared: Ingredient mg/capsule Ferrous fumarate 150 Hydroxypropylmethylcellulose, 4000 cps 1Q0 Lactose 100 Talc 40 Magnesium stearate 10 Total 400 The ferrous fumarate, hydroxypropylmethylcellulose and lactose were homogeneously mixed and passed through a comminuting machine with a No. 0 plate at medium speed and with - 20 43083 knives forward. The talc and magnesium stearate were mixed with an aliquot of the initial mixture, screened through a 60 mesh screen and then added to the remainder of the initial powder mixture. The formulation was then mixed for a further 15 minutes and filled into No. 1 capsules.

The dissolution rate of the capsules was determined in gastric fluid by modified NF method using rotating bottles at 40 r.p.m. The results are set forth in Table III.

TABLE 111 Percentage of Active Medicament Released Time (hours) Gastric fluid (pH 1.2) 0 0 1 45 2 85.7 3 98.6 The capsule shapes remained buoyant throught the test. The release of ferrous fumarate from capsules tested in pH change medium was very poor due to the low solubility of ferrous fumarate in relatively higher pH media. Such test results represent the effect of ferrous fumarate in conventional sustained-release formulations which are not retained in the stomach.

Example 3 Sustained-release antacid capsules containing the following ingredients were prepared: Ingredient mg/capsule FMA-11* 254.7 Magnesium oxide, light 127.0 Lactose, hydrous .3 Hydroxypropylmethylcellulose, 4000 cps 63.0 Gum karaya, Stein Hall Talc, tablet grade 31.0 24.0 Magnesium stearate .0 Total 525.0 *Aluminium hydroxide/magnesium carbonate co-precipitate Reheis Co., Berkley Heights, New Jersey.

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 machine using a No. 1 plate at medium speed and with knives forward. The mixture was then slugged on a suitable press using 0.75 inch F.K. punches and the slugs were milled on a comminuting machine at medium speed using a No, 1 plate with knives forward. The resulting granules were thoroughly mixed with the remaining ingredients and filled into No. 0 capsules using conventional capsule 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 0.1-N hydrochloric acid in a stoppered flask rotated at 40 r.p.m. A 50 ml sample is withdrawn at a specified time and titrated with 0.1-N sodium hydroxide to pH 3.5 which is the neutralisation point given in the Federal 4 308 3 Register for acid neutralising capacity consumed· was calculated from the sample given.in.Table TV. The capsule shapes The amount of acid The results are remained floating throughout the test.

TABLE IV Time Antacid Release 1st hour 42.1% 2nd hour 96.7% 3rd hour 104% Example 4 Sustained-release aspirin capsules containing the following ingredients were prepared: ingredient mg/capsule Acetylsalicyclic acid, micronised 400 Dicalcium phosphate, anhydrous 20 Hydroxypropylcellulose 40 Tragacanth 100 Total 560 All ingredients except th.e tragacanth were thoroughly mixed and passed through a comminuting machine using a No. 00 plate with 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 capsule shapes were found to remain buoyant in the gastric fluid.

Example 5 Sustained-release capsules containing the following ingredients were prepared: Ingredient mg/capsule Riboflavin, type S* 15 Hydroxypropylmethylcellulose 110 Lactose 120 Talc 30 Magnesium stearate 5 Total 280 *A type of riboflavin characterised by being less soluble and more crystalline than riboflavin phosphate All ingredients were thoroughly mixed and filled into No. 2 gelatin capsules. The release rate in gastric fluid was determined by the modified NF method at 40 r.p,m. The results are set forth in Table V.

TABLE V Time (hours) S Active Medicament Released 0.5 34 1 45.3 2 62.6 3.5 84.7 5 92.6 The capsule shapes remained floating throughout the experiment.

Example 6 Sustained-release capsules ingredients were prepared: Ingredient Riboflavin, type s Guar gum Mannitol powder Corn starch Tragacanth containing the following mg/capsule 100 Total 280- All ingredients except the tragacanth were combined and mixed in a suitable mixer. The resulting mixture was granulated with a mixture of equal parts of water and ethyl adcohol The wet granulation Was passed through a comminuting machine using a No. 3 plate witji knives forward. The granulation was then dried at 110°F and again passed through a Fitzpatrick comminuting machine using a No. 0 plate with knives forward.

The tragacanth was added dry to the granulation, the whole was thoroughly mixed and filled into No. 2 gelatin capsules. The release rate of the capsules was determined by the modified NF method at 40 r.p.m. The results are set forth in Table VI.

TABLE VI Time (hours) % Active Medicament Released 0.5 54.5 1 59.5 2 65.6 3.5 78.5 5 88.8 The capsule shapes remained floating throughout the experiment.

Example 7 Riboflavin tablets were prepared from formulation: Ingredient Riboflavin-5'-phosphate sodium* Methylcellulose, 4000 cps Mannitol Sodium carboxyrnethylcellulose, high viscosity, degree of substitution 0.38-0.48 Hydroxypropylmethylcellulose 4000 cps Polyvinylpyrrolidone Ethylcellulose 10 cps Talc Magnesium stearate the following mg/tablet 21.4 70.0 .0 110.0 60.0 .0 80.6 .0 3.0 Total 400.0 *Contains 2% by weight excess.

The riboflavin and sodium carboxyrnethylcellulose were thoroughly mixed and granulated with the polyvinylpyrrolidone - 26 4 3 0 8 3 as a 10% by weight solution in alcohol. The remaining ingredients with the exception of the talc and magnesium stearate were thoroughly mixed and passed through a comminuting machine using a No. 1 screen with hammers forward. The dried granulation was combined with the mixture and thoroughly mixed. The talc and magnesium stearate were then added and the total mixture was homogeneously blended and compressed into tablets using standard concave punches. The tablets were compressed to a hardness of 4-6 s.c.u. and it was determined that the hardness should not exceed 10 s.c.u. it was found that tablets at 4 s.c.u. would float instantly on artificial gastric fluid, whereas tablets at 6 s.c.u. would sink temporarily before rising to the surface. Tablets at 10 s.c.u. were not buoyant.

For control purposes, gelatin capsules were filled with the following formulation: Ingredient mg/capsule Riboflavin-5'-phosphate sodium 21.4 Corn starch 73.6 Lactose, hydrous 150.0 Talc 30.0 Magnesium stearate 5.0 Total 280.0 In vitro release tests were carried out by the modified 25 N.F. method in gastric fluid only at 40 r.p.m. The results are set forth in Table VII.

TABLE VII Percentage Active Medicament Released Time (hours) Average Range 0.5 32 27-40 1 49 39-59 2 76 55-87 3.5 91 87-95 5 104 95-108 100 per cent of the riboflavin contained in a control capsule was released With 0.5 hour.

An in vivo test was conducted using five volunteers.

The dosage forms were administered about 1.5 hours after breakfast. ·Periodic urine samples were analysed for recovery of riboflavin which is an index of absorption. The results are given in Table VIII.

TABLE VIII Time Interval (hours) Mg of riboflavin excreted due to dose (Mean) . Control SR Tablet 0-2 2.03 0.98 2-4 2.11 1.79 4-6 0.84 1.14 6-8 0.47 1.14 8-12 0.84 3,23 12-24 0.38 1.86 6.87 10.14 - 28 4 3 0 8 3 Percentage of Dose Excreted in 25 hours: Control: 44% SR tablet: 67.5% The results of this experiment clearly indicate that the sustained-releas'e (SR) tablet containing riboflavin was retained in the stomach since the absorption of riboflavin occurs only from the proximal end of the small intestine. The results clearly indicate that riboflavin is continuously available from the sustained-release tablet to the appropriate site of absorption for a prolonged period. The second pronounced peak of riboflavin from the tablet might be due to enterohepatic circulation which, according to the literature, may be attributable to a concentration dependent relationship in handling of riboflavin by the liver.

Example 8 Sustained-release aspirin tablets containing 7.5 grains aspirin were prepared from the following granulations: Granulation A Acetylsalicyclic acid Hydroxypropylmethylcellulose, 400 cps mg 500 125 3 628 20 Hydroxypropylmethylcellulose, 15 cps Total Granulation B Calcium carbonate, precipitated 65 Magnesium carbonate 20 25 Mannitol 10 Carboxymethylcellulose 2 Total 97 3 0 8 3 The two granulations were homogeneously mixed with 5 mg of 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 tablets to remain buoyant.

Example 9 Sustained-release two-layered antacid tablets were prepared from the following ingredients: Layer A-Immedlate Release Ingredient mg/tablet FMA-11* 160.0 Methylcellulose 5.8 Magnesium oxide 80.0 Primojel** 10.0 Magnesium stearate 2.5 Total 258.3 *Aluminium hydroxide/magnesium carbonate co-precipitate Reheis Co.

**Sodium carboxymethyl starch - E. Mendel & Co., Carmel, New York The FMA-11 and magnesium oxide were mixed in a suitable mixer. The resulting mixture was granulated using a 2.5% by weight solution of the methylcellulose in a mixture of equal parts of water and ethyl alcohol. The granulation was dried overnight at 60°C. The dried granulation was then milled, combined with the Primojel and magnesium stearate and mixed for 5 minutes. The resulting homogeneous mixture was then compressed on a conventional two-layer tablet press.

Layer B-Sustained Release Ingredient mg/tablet FMA-11 170 Magnesium oxide Methylcellulose 4000 cps (dry) Methylcellulose 4000 cps (wet) Ethylcellulose Direct compression grade starch Syloid* (registered Trade Mark) Magnesium stearate Total 529 ♦Purified silicon dioxide - W. R. Grace & Co., Baltimore, Maryland The FMS-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 of water and ethyl alcohol and the granulation dried ' overnight at 60°C. 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 a further 5 minutes. This mixture was then compressed on a conventional two-layer tabletting machine with Layer A to a standard concave capsule shape 3/4 x 5/16. The acceptable hardness of the tablets was between 12 and 14 s.c.u. and it was found that the hardness should 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 - 31 43083 with a magnetic stirrer running at slow speed. '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 2 hours slowly releasing medicament.

Claims (26)

CLAIMS:

1. A sustained-release pharmaceutical formulation in solid dosage form for oral administration, which formulation comprises a homogeneous mixture of one or more medicaments, 0 to 80% by weight of one or more therapeutically inert, pharmaceutically acceptable adjunct materials, 0 to 60% by weight of one or more edible fatty materials having a specific gravity of less than 1 and one or more hydrocolloid or hydrocolloids being incorporated in the mixture by combining said hydrocolloid(s) in dry, particulate form with another ingredient or mixture of ingredients in a dry and essentially non-liquid state whereby the hydrocolloid(s) so incorporated retain said dry, particulate form, and any subsequent treatment being in a dry and essentially nonliquid state whereby the solid dosage form is prepared from a homogeneous mixture containing the hydrocolloid(s) so incorporated in dry, particulate form so .that when the mixture is in contact with gastric fluid the hydrocolloid(s) so incorporated forms by hydration a water impermeable barrier, which barrier by sequential erosion thereof by the gastric fluid and reformation as fresh hydrocolloid(s) so incorporated is exposed allows slow release of medicament, the proportion of hydrocolloid(s) so incorporated and the other ingredients being chosen whereby the said hydrocolloid(s) upon hydration in gastric fluid provides a solid dosage form which floats in gastric fluid.

2. A sustained-release pharmaceutical formulation in accordance with claim 1, wherein the solid dosage form is a tablet.

3. A sustained-release pharmaceutical formulation in accordance with claim 1, wherein the solid dosage form is a capsule. 4. To 11 when dependent on claim 2, or claim 12.

4. A sustained-release formulation in accordance

5. ) A sustained-release formulation in accordance with claim 4, wherein said hydrocolloid(s) comprises from 20% by weight to 75% by weight of said formulation. 5 with any one of claims 1 to 3, wherein said hydrocolloid(s) comprises from 5% by Weight to 99.9% by weight of said formulation.

6. ) A sustained-release formulation in accordance with any 5 one of claims 1 to 5. wherein said fatty material(s) comprises from 5% by weight to 30% by weight of said formulation.

7. ) A sustained-release formulation in accordance with any one of claims 1 to 6, wherein said hydrocolloid is

8. ) A sustained-release formulation in accordance with claim 7, wherein said hydrocolloid is hydroxypropylmethylcellulose.

9. , wherein said benzodiazepine is chlordiazepoxide,. diazepam,

10. , wherein said benzodiazepine is chlordiazepoxide. 430 8 3 10) A sustained-release formulation in accordance with claim 10 methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose or a mixture thereof.

11. ) A sustained-release formulation in accordance with claim

12. A sustained-release tablet in accordance with claim 2, or any one of claims 4 to 8 when dependent on claim 2, wherein said medicament comprises one or more antacid compounds.

13. A sustained-release formulation consisting of a two-layered tablet comprising a first layer containing one or more medicaments and therapeutically inert pharmaceutically acceptable adjunct materials free from sustained-release ingredients and a second layer comprising a tablet in accordance with claim 2, and any one of claims

14. A two-layer tablet in accordance with claim 13, wherein said medicament is one or more antacid substances.

15. A sustained-release capsule in accordance with claim 3, wherein said medicament is a benzodiazepine. 15 9) A sustained-release formulation in accordance with any one of claims 1 to 8 inclusive, wherein said medicament is a benzodiazepine.

16. A sustained-release capsule in accordance with claim 15, wherein said benzodiazepine is chlordiazepoxide, diazepam, oxazepam or bromazepam.

17. A sustained-release capsule in accordance with claim 16, wherein said benzodiazepine is chlordiazepoxide.

18. A process for the manufacture of a sustained-release pharmaceutical formulation In accordance with any one of claims 1 to 12 and 15 to 17, which process comprises forming a dry, essentially non-liquid homogeneous mixture by mixing together said medicament(s), hydrocolloid(s) in dry particulate form, and any said adjunct(s) and/or said edible fatty material(s) and bringing the mixture directly into a solid dosage form.

19. A process in accordance with claim 18, wherein said medicament(s) and hydrocolloid(s) are blended together and said adjunct (s) and/or edible fatty material(s) are added to the blend.

20. A process in accordance with claim 19, wherein the blending of said medicament(s) and said hydrocolloid (s) is by a dry granulation technique. 20 oxazepam or bromazepam.

21. A process for the manufacture of a sustained-release pharmaceutical formulation in accordance with any one of claims 1 to 12 and 15 to 17, which process comprises blending together said medicament(s), adjunct(s) and/or edible fatty material(s) to form a dry, essentially nonliquid blend, mixing said hydrocolloid(s) in dry particulate form with the blend, effecting any further process steps in a dry, essentially non-liquid state, and bringing the resulting mixture into a solid dosage form.

22. A process in accordance with claim 21, wherein the blending· is by a granulation technique.

23. A process in accordance with claim 22, wherein the granulation is wet granulation with subsequent drying.

24. A process in accordance with any one of claims 18 to 23, wherein the solid dosage form is a tablet and there is prepared therefrom a two-layered tablet by addition of a layer containing one or more medicaments and therapeutically inert pharmaceutically acceptable adjunct material free from sustained-release ingredients.

25. A process for the manufacture of a sustained-release pharmaceutical formulation in accordance with claim 1 or claim 13, substantially as hereinbefore described with reference to any one of the foregoing Examples.

26. A sustained-release pharmaceutical formulation in accordance with claim 1 or claim 3, when manufactured by a process in accordance with any one of claims 18 to 25.