CA1269043A - Floating sustained release therapeutic compositions - Google Patents

Abstract

FLOATING SUSTAINED RELEASE
THERAPEUTIC COMPOSITIONS

ABSTRACT OF THE DISCLOSURE

Sustained release tablets which will float on gastric juice are described. They comprise a hydrocolloid gelling agent such as agar, a therapeutically acceptable inert oil, the selected therapeutic agent and water.

Description

~2690~3 FIELD OF THE INVENTION

This invention relates to therapeutic compositions in dosage unit form which are capable of floating on gastric juice and delivering their contained therapeutic agent over S an extended period of time.

BACKGROUND OF THE INVENTION

The convenience of administering a single dose of a medication which releases active ingredients 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 arts. The advantage to the patient and clinician in having consistent and uniform blood levels of medication over an extended period of time are likewise recognized.
The conventional approaches to sustained release can be disadvantageous when the medicament is administered orally because 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. Penicillin for example is fully absorbed at one point in the intestine. Once the dosage unit containing penicillin passes this point under the influence of peristaltic movement, the remaining penicillin is not absorbed into the blood stream, but is merely excreted, .

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~269043 Most medicaments will undergo varying degrees of change in solubility by passage from the strongly acid conditions of the stomach to the neutral and to the alkaline conditions of the intestines. Additionally there are medicaments, e.g.
antacids which are intended to act in the stomach and there-fore lose most beneficial properties when they pass into the intestine.
The advantages of sustained release dosage forms, which are retained in the stomach, for example by floating in the gastric juice, slowly releasing their therapeutic contents into the gastric juice for passage through the intestinal tract will be readily apparent. These include (1) increased contact time for local activity in the stomach where such is required, as in the treatment of stomach ulcers, (2) increased and more efficient absorption for drugs such as penicillin which havespecific absorption sites, and (3) the ability to limit the number of dosages.
Many attempts have been made to provide therapeutic dosage forms which will float on the gastric juice and have sustained release capabilities. A series of United States Patents 4,126,672; 4,140,755 and 4,167,558 describes compressed tablets and capsules containing hydrophilic colloids as carriers for the therapeutic agents. The products are said to be in hydrophilic balance so that when they are first ingested they sink to the bottom of the gastric juice. As they absorb water they become more buoyant, rise to the top and float. However, once the tablet is at the lower end of the stomach, its rise to the top might be impeded by food particles in the stomach, or it might pass through the pylorus into the intestine before it attains sufficient buoyancy to float.

12690~3 Nakano et al in a series o papers, J. Pharm. Pharmacal., 31, 869 ~1979); Chem. Pharm. Bull., 28(10), 2905 (1980); and Chem. Pharm. Bull., 27(11), 2834 (1979) have described sustained release therapeutic beads formed from rather con-centrated agar solutions containing a therapeutic agent.
.There is no description of the density of the beads or whether they will float.
United States Patent 4,434,153 to Urquahart and Theeuwes describes slow release tiny pills which are slow release because they are coated and embedded in a hydrophilic matrix which swells in contact with water, Mitra in United States Patent 4,451,260 describes a 1exible, thin, water soluble inert carrier sheet or film which contains a drug. The sheet may have an additional barrier on one or both sides. Air spaces are introduced during the manufacturing process causing the material to become buoyant. The sheets are made of synthetic polymers and various excipients may be incorporated to effect dis-solution or release of the drug. The matrix does not swell but is flexible. The drug is administered by cutting of an appropriate piece of the film and folding it into a capsule, when the capsule dissolves, the sheet is left to float on the gastric fluids.
Despite the major efforts that have been applied to the problem no completely satisfactory products have yet been produced.

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THE INVENTION
Therapeutic dosage unit forms have now been discovered which are easy to prepare, provide sustained release of con-tained therapeutic agents and float on gastric juice. These tablets, although not compressed, have sufficient mechanical stability so that they will stand up to the normal stress of production, packaging and dispensing. They have a density which is less than one and sufficiently low so that they will float on gastric juice. Typically the density is from about 0.6 to 0.95.
According to the invention, as claimed herein, there is provided a therapeutic composition in dosage unit form as a non-compressed tablet having a density of less than one and capable of floating on gastric juice in vlvo comprising a matrix formed from a gelling agent containing a therapeutic agent, a therapeutically acceptable inert oil and water in the following percentages by weight based on the total weight:
gelling agent 0.5 to 4%; oil 12 to 20%; therapeutic agent 50 to 75%; and the balance water.
The tablets contain as essential ingredients, the thera-peutic agent in sufficient concentration to be therapeutically effective, a gelling agent, a therapeutically acceptable inert oil and water.
The optimum concentration of the therapeutic agent in the final product will of course vary with the identity of the agent and its optimum therapeutic dosage. Generally the amount of the agent in the dry tablet will be from about 50 to 75~ by weight based on the total weight. (All percentages by weight in this disclosure and claims are based on total weight.) It will be apparent to those skilled in the art that there can be appreciable variation from these parameters especially the range of therapeutic agent without undue effect.
Theophylline is a typical drug which can be usefully dis-pensed from the tablets of this invention. It is a broncho-dilator which has been used for the management of chronic as-thma for prophylactic purposes. Its plasma half life has been reported to be 4.4 to 6.2 hours. In order to obtain and re-tain effective plasma theophylline concentrations, a .

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dose of 200 to 300 mg of theophylline is admlnistered three or four times daily. The rapid absorption and elimination characteristics of theophylline results in large variations in plasma theophylline concentration during treatment of patients receiving chronic therapy. Therefore it is a prime candidate for the sustained release, floating tablets of this invention.
Except for those which must be protected from the gastric juice, there is practically no limitation to the therapeutic agents which can be administered in accordance with this invention. They include J for example, analgesics J anorexics, antacids J antibiotics J antidiabetics J antihistamines J steroids J
antinauseants J antispasmodics J cardiovascular preparations, decongestants, diuretics, geriatrics, muscle relaxants,tranquil-izers and vitamins. More specific examples include acetaminophen, ampicillin, atropine J penicillin J tetracycline J chlorathiazide J
phenytoinJ riboflavinJ quinidine, cemetidine, indomethicin, pred-nisolone and estradiol. The agents can be employed as free bases or as metal or acid addition salts.
The preferred gelling agent is agar although other gelling agents may be used. These include for example, agarose J cara-geeninJ konjac gumJ alginic acid and its salts, cellulose derivatives, carbopol and starch. The concentration of gelling agent in the final product is about 0.5 to 2% by weight.
Mixtures of gelling agents may be employed.
The preferred therapeutically acceptable inert oil is mineral oilJ specifically light mineral oil which ordinarily has a density of from 0.828 to 0.880. Other hydrocarbon or 126gO~3 vegetable oils can also be employed. Inert waxes may also be useful. The concentration of the oil in the initial mixture before gelling is from about 8% to 30%. The term "inert`' means chemically inert, that is it does not react with any of the components of the tablet.
The finished products may also contain other conventional additives such as thickening agents, surfactants, preservatives, bulking agents or antio~idants.
The tablets of this invention are sustained release dosage units, that is they release their medicaments over an extended period of time. The actual rate of release varies with the amount of exposed surface area, and therefore with size and shape of the tablet. The tablets have a density less than one and will float on gastric juice in vivo. Typically, the density is from about 0.6 to 0.95.
Typically, the concentration of the components;inthe final product as it is provided in dosage unit form is:
gelling agent, 0.5 to 4%; oil 12 to 20%; therapeutic agent 50 to 75%; balance water.
The tablets of the invention are typically prepared by the ollowing steps:
1. Prepare a solution of the hydrocolloid gelling agent in warm water.

2. Add the selected therapeutic agent to the selected oil.

3. Mix 1 and 2 and cool but not to the point where gelation takes place. This can be determined separately by simple testing.

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4 Pour theemulsions which result from the cooling and stirring into tablet molds and let stand until the gel forms.

5. Dry.
Several variations of this procedure are possible as will be readily apparent tothose skilled in the art.
During the gelation and drying steps most of the water evaporates. The resulting product, although it is not compressed, is a hard tablet in the shape of the mold. Its compression strength is comparable to that of most commercially available therapeutic tablets. It is characterized by a network of multitudinous air holes and passages.
The concentration of the various components in the starting mixture is 0.5 to 2% gelling agent, 8 to 15% thera-peutically acceptable inert oil, 25 to 50% therapeutic agent, balance water. As indicated above, the exact amount of therapeutic agent may vary appreciably.
With agar, the solution temperature is about 70C to 100C and the pour temperature is about 50C to 70C. These are generally the same temperature ranges employed with other gelling agents.
It is surprising to find that such small quantities of gelling agents are capable of forming such rugged tablets without compression.
The following examples are given by way of illustration only and are not to be considered limitations of this invention, many apparent variations of which are possible without departing from the spirit or scope thereof.

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Nine grams of theophylline was mixed with 2 grams of light mineral oil in a beaker and stirred. In a separate beaker 10 ml of water was adde~ to 0.2 grams of agar, stirred with a magnetic stirrer and heated to boiling. The mixture was cooled to 70C and gradually added to the theophylline-oil mixture with vigorous stirring to form an oil in water emulsion. The warm emulsion was poured into a mold plate with plurality of hollow cylindrical molds each with a height of about 0.46cm and a diameter of about 1.10cm. The compositions were allowed to cool and gel (about 5 minutes).
The tablets were removed from the mold and dried. The density of the tablets varied slightly amongst themselves but the average was about 0.70. This product, Formulation 1, had the following starting composition.

Theophylline 9 grams Light Mineral Oil 2 grams Water 10ml Agar 0.2 grams 12690~3 EX`AMPLE 2 Example 1 was repeated to produce the following Formulation 2.
Theophylline 9 grams Light Mineral Oil 3 grams Water lOml Agar 0.2 grams The density of ten tablets prepared from Formulation 2 was carefully measured. It varied from 0.6943 to 0.7483.
The average density was 0.7178. The average weight of the dried tablets was 317 mg, and each contained about:

Theophylline237mg Light Mineral Oil 60mg Agar 5.3mg Water 14.7mg The di~solution of theophylline from tablets formed from Formulations 1 and 2 was determined by the standard USP Basket mechod at 50 RPM. The results are shown below where the values given are percent release of theophylline.

r - -Time ~ 1.2 ¦ 7.4 pH 1.2 1 7.4 _ ~.
1 23.8 j 26.1 21.0 20.4 2 31.4 ! 36.7 4 43.4 1 50.3 38.5 37.7

6 54.8 53.4 8 65.1 ~ 65.9 2 ~ 80.0 75.9 74.9 19 1 ~ 91.~ 91.2 t It is apparent from these values that the tablets release their theophylline content over an extended period of time.

~26~t043 Plasma concentrations of theophylline in a human adult male volunteer were determined after ingestion of a single 237mg tablet of Formulation 2. The values 5are given below.

TIME (hours) CONCENTRATION (mcg/ml) 3 1.7 6 1.95 12 2.7 24 3.2 The sustained release effect is evident from the figures.

SUPPLEMENTARY DISCLOSURE
In the foregoing description, certain prior art has been acknowledged. It is also known that Boraie and Naggar in Acta Pharm. Jugosl., 34, 247 (1984) disclose a procedure for preparing non-compressed tablets which involves preparing an aqueous suspension containing at least 7.5% agar and a medicament such as theophylline, at an agar/drug ratio of 1/0.5 to 1/1.33, and charging said suspension into a tablet mold and cooling. The molded tablets are removed from the mold and dried. The dried tablets have an agar content of at least 43%. There is no indication of the density of the dried tablets or whether they will float on gas-tric fluid.

~ ~690~3 It is noteworthy that, although U.S. patent 4,167,558 discloses the preparation of compressed tablets and capsules which float on gastric fluid, it specifically cautions against the use of water or other solvent for the hydro-5 colloid by the statement that "In the practice of the in-vention, the hydrocolloid is incorporated into the formula-tion in dry form...Wherein a hydrocolloid such as described herein is combined in the formulation in the presence of a solvent, such hydrocolloid does not function to facilitate the buoyancy of the tablets prepared therefrom". As a fur-ther feature of this invention, it has been found that the tablets o~ this invention preferably contain from 10 to 20%
by weight, more particularly from 12 to 20% by weight, of a thera-peutically acceptable inert oil in association with about 0.5 to 4% by weight of a gelling agent, from 50 to 75% by weight of a therapeutic agent and the balance water.
The gelling agents which may be used in the present invention may be one or more of the gelling agents herein before described. Additional suitable selling agents may be locust bean gum and modified natural products such as certain water-swellable cellulose derivatives and synthetic products such a polyacrylic acid and the like.
The low concentration of gelling agents which are effective in the tablets of this invention are unexpected in view of the significantly higher concentrations disclosed in the prior art in both compressed and non-compressed tablets as well as capsules, gels and beads.
When preparing the aqueous mixture prior to pouring into a tablet mold and allowing to gel, the concentration of the various components in the aqueous mixture may be, for example from 0.5 to 2% of gelling agent, from 5 to 30%
of therapeutically acceptable inert oil, from 25 to 50% of therapeutic agent and the balance is water. The exact amount of therapeutic agent may vary appreciably, depending upon the effective therapeutic doseage.

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~26aO ~3 Theophylline tablets were prepared as described in Example 1 using agar as the gelling agent, in the following formulation:

Ingredients grams %
Theophylline 6.0 33.0 Mineral oil 2.0 11.0 Agar 0.2 1.1 Water 10.0 54.9 The molded gel tablets were air dried for 24 hours.
The size of the dry tablet was 1.11 x 0.48 cm and the average weight was 231 mg per tablet. The tablet hardness, determined with a Pfizer hardness tester, was 6.1 kg and the average tablet density was 0.560.
The dissolution test was carried out by the basket method at 50 rpm and 37C in a O.lN HCl dissolution medium (pH 1.3). The floating tablets had the following release pattern:

Time, hours% ReleasedCumulative %

Theophylline tablets were prepared as described in Example 1, using iota carrageenan as the gelling agent, in the following formulation:

':.. ' ' , ~ ', ,' '` . ' -, 12690~3 Ingredientsgrams Theophylline 6.0 32.8 Iota carrageenan 0.3 1.6 Mineral oil 2.0 10.9 Water 10.0 54.6 After 24 hours air drying, the 1.11 x 0.48 cm tablet weighed 234 mg, the hardness was 6.2 kg and the density was 0.576.
The dissolution test was conducted in O.lN HCl (pH
1.3) at 50 rpm at 37C. The floating tablets had the following release pattern:

Time, hours % Released Cumulative %

Theophylline tablets were prepared as described in Example 1, using kappa carrageenan as the gelling agent, in the following formulation:

Ingredients grams %
Theophylline 6.0 32.8 Kappa carrageenan 0.3 1.6 25Mineral oil 2.0 10.9 Water 10.0 54.6 After 24 hours air drying, the 1.11 x 0.48 cm tablet weighed 237 mg, the hardness was 5.2 kg and the density was 0.580.
The dissolution test was conducted in O.lN HCl (pH
1.3) at 50 rpm and 37C. The floating tablets had the following release pattern:

'~' " , lX~i~G43 Time, hours ~ Released Cumulative %
_ __ _ Theophylline tablets were prepared as described in Example 1, using a mixture of kappa carrageenan and locust bean gum as gelling agent in the following formulation:

Ingredients grams %
Theophylline 6.0 33.0 Kappa carrageenan 0.1 0.5 Locust bean gum 0.1 0.5 15 Mineral oil 2.0 11.0 Water 10.0 54.9 After 24 hours air drying, the 1.11 x 0.48 cm tablet weighed 224 mg and the hardness was 5.6 kg. The density of the tablet was 0.562.
The dissolution test was carried out in O.lN Hcl (pH
1.3) at 50 rpm and 37C. The floating tablets had the following release pattern:

Time, hours % Released Cumulative

7 87 Theophylline tablets were prepared as described in Example 1, using a mixture of iota carrageenan and locust bean gum as gelling agent in the following formulation:

i90~3 Ingredients grams %
Theophylline6.0 32.8 Iota carrageenan 0.2 1.1 Locust bean gum 0.1 0.5 Mineral oil 2.0 10.9 Water 10.0 54.6 After 24 hours air drying, the 1.11 x 0.48 cm tablet weighed 221 mg, the hardness was 7.9 kg and the density was 0.546.
The diss~ution test was conducted in O.lN HCl (pH
1.3) at 50 rpm and 37C. The floating tablets had the following release pattern:

Time! hours~ ReleasedCumulative %

8 5 63 Theophylline tablets were prepared as described in Example 1, using a mixture of alginic acid and locust bean gum as gelling agent, in the following formulation:

Ingredientsgrams Theophylline6.0 32.8 Alginic acid0.2 1.1 Locust bean gum 0.1 0.5 Mineral oil 2.0 10.9 Water 10.0 54.6 . ~ .

12690~3 After 24 hours air drying, the 1.11 x 0.48 cm ta~let weighed 226 mg and the hardness was 7.4 kg. The density of the tablet was 0.554.
The dissolution test was conducted in O.lN HCl tpH
1.3) at50 rpm and 37C. The floating tablets had the following release pattern:

Time, hours% Released Cumulative %
1 20.2 20.2 2 7.7 27.9 3 6.8 34.7 4 4.4 39.1 4.7 43.8 6 4.1 47.9 8 6.2 54.1 5.5 59.6 12 5.0 64.6 Ampicillin floating tablets were prepared using agar as the gelling agent, according to the following formulation:

Ingredients grams %
Ampicillin, anhydrous 90.0 32.5 Light mineral oil 16.0 5.8 Agar 3.2 1.15 Sodium citrate8.0 2.9 Water 160.0 57.7 This formulation was used to make a batch of 300 tablets. The mineral oil was added to the ampicillin previously charged into a 500 ml beaker and mixed thoroughly with a glass rod. In a separate beaker, the water was heated to 90C and the sodium citrate was dis-solved therein with stirring. The agar was added to the aqueous solution and stirred while heating until the agar dissolved. The ampicillin-oil mixture which was in the form 12690~3 of a powder was added in portions to the agar solution at 70C and mixed with an electric whisk until a smooth, creamy suspension was obtained. The suspension was poured into a tablet mold at 48-50C. The suspension gelled after cooling for lO minutes. The excess was scraped off the top of the molds, the tablets were pushed out of the molds and air dried at room temperature for 24 hours.
The average weight of the l.ll x 0.635 cm tablets was 423 mg and the density was 0.69. The hardness was 11.7 kg and the friability was 0.9%. The dissolution test was carried out in water at lO0 rpm and 37C. The floating tablets had the following release pattern:

Time, hours~ ReleasedCumulative %
1 17.8 17.8 2 9.9 27.7 3 7.0 34.7 4 5.8 40.5 4.4 44.9 6 4.7 49.6 7 3.1 52.7 8 2.6 55.3 5.1 60.4 12 3.2 63.6 14 5.5 69.1 16 3.4 72.5 18 4.6 77.1 Ampicillin floating tablets were prepared by the following formulation using agar as the gelling agent:

Ingredients grams %
Ampicillin, anhydrous 6.0 32.1 Light mineral oil 2.0 10.7 Agar 0.2 1.1 Sodium citrate 0.5 2.7 Water 10.0 53-5 ~''' '' ~ . ' ~.269043 The tablets were prepared in the same manner as described in Example 12. The dissolution test on the air dried tablets was conducted in water at 50 rpm and 37C.
The floating tablets had the following release pattern:

Time, hours% ReleasedCumulative %
2 16.9 16.9 4 10.8 27.7 6 10.0 36.7 8 6.6 43.3 4.9 48.2 12 6.0 54.2 Captopril tablets were prepared in the same manner as described in Example 12, using agar as gelling agent, according to the following recipe:

Ingredients grams %
Captopril 7.0 35.7 Light mineral oil 1.0 5.1 Agar 0.3 1.5 Lactose 1.0 5.1 Calcium gluconate 0.3 1.5 Water 10.0 51.0 The captopril-oil mixture was added to the aqueous solution containing agar, lactose and calcium gluconate at 70C and after mixing thoroughly was poured into the tablet mold at 50C. The molded gel tablets were air dried for 36 hours. The size of the dried tablet was 0.95 x 0.32 cm and the average tablet weight was 134 mg. The hardness was 9.9 kg and the average tablet density was 0.817. A friability test showed a loss of 0.84%.
The dissolution test was carried out by the U.S.P.
basket method at 50 rpm and 37C using a dissolution medium containing O.lN HCl and 0.001% ethylenediaminetet-raacetic acid. The floating tablets showed the following release pattern:

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1 63.7 63.7 2 24.2 87.9 3 7.2 95.1 4 4.6 99.7 Captopril tablets were prepared in the same manner as described in Example 12, using agar as gelling agent, in the following formulation:

Ingredients _rams %
Captopril 7.0 36.3 Light mineral oil 2.0 10.4 Agar 0.3 1.5 Water 10.0 51.8 The molded gel tablets were air dried for 24 hours.
The size of the dried tablets was 0.95 x 0.32 cm and the average weight was 125 mg per tablet. The tablet hardness was 6.2 kg and the tablet density averaged 0.690.
The foregoing is exemplary and illustrative of compositions and products responding to the present in-vention, but it is to be understood that they are not limitative since many active medicaments of various types, many different gelling agents and many different oils can be employed in the new non-compressed tablets.

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Claims (31)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A therapeutic composition in dosage unit form as a non-compressed tablet having a density of less than one and capable of floating on gastric juice in vivo comprising a matrix formed from a gelling agent containing a therapeutic agent, a therapeutically acceptable inert oil and water in the following percentages by weight based on the total weight:
gelling agent 0.5 to 4%; oil 12 to 20%; therapeutic agent 50 to 75%; balance water.

2. The composition according to claim 1 wherein the gelling agent is one or more agents selected from the group consisting of agar, carrageenan and alginic acid.

3. The composition of claim 1 wherein the gelling agent is agar.

4. The composition of claim 1, 2 or 3 wherein the ther-apeutic agent is theophylline.

5. The composition of claim 1, 2 or 3 wherein the inert oil is mineral oil.

6. The composition of claim 1 wherein the gelling agent is agar, the therapeutic agent is theophylline and the inert oil is mineral oil.

7. A therapeutic composition in unit dosage form as a non-compressed tablet having a density of less than one-and capable of floating on gastric fluid in vivo comprising a matrix formed from a gelling agent containing theophylline, a therapeutically acceptable inert oil and water in the fol-lowing percentages by weight based on the total weight of the tablet: gelling agent 0.5 to 4%; oil 12 to 20%; theo-phylline 50 to 75%; balance water.

8. The composition according to claim 7 in which the gelling agent is one or more agents selected from the group consisting of agar, carrageenan and alginic acid.

9. A method of forming a non-compressed tablet having a network of multitudinous air holes and passages therein, and a density of less than one and capable of floating on gastric fluid in vivo which comprises:
(1) forming a solution of a gelling agent in water, (2) forming a first mixture containing a therapeutic agent and a therapeutically acceptable inert oil, (3) cooling said solution, but not to the point where gelation takes place, (4) combining the solution and the first mixture to produce a second mixture containing from 0.5 to 2% of gelling agent, 8 to 30% of oil, 25 to 50% of therapeutic agent and the balance water, all by weight based on the total weight, (5) pouring the second mixture into a tablet mold and letting it stand in the mold to form a gel, and (6) drying the molded gel tablet to reduce the water content.

10. The method according to claim 9 wherein the gelling agent is one or more agents selected from the group consisting of agar, carrageenan and alginic acid.

11. The method according to claim 9 or 10 wherein the therapeutic agent is theophylline.

12. The method according to claim 9 wherein there is used as starting materials 0.2 part of agar as gelling agent, 9 parts of theophylline as therapeutic agent, 2 parts of light mineral oil as the therapeutically acceptable inert oil and 10 parts of water to produce the second mixture.

13. The method according to claim 9 wherein there is used as starting materials 0.2 part agar as gelling agent, 9 parts of theophylline as therapeutic agent, 3 parts of light mineral oil as the therapeutic acceptable inert oil and 10 parts of water to produce the second mixture.

14. The composition according to claim 1 wherein there is present 237 parts by weight of theophylline, 60 parts by weight of light mineral oil, 5.3 parts by weight of agar and 14.7 parts by weight of water.

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE

15. A therapeutic composition in unit dosage form as a non-compressed tablet having a density of less than one and capable of floating on gastric fluid in vivo comprising a matrix formed from a gelling agent containing a therapeutic agent, a therapeutically acceptable inert oil and water in the following percentages by weight based on the total weight of the tablet: gelling agent 0.5 to 4%; oil 10 to 20%;
therapeutic agent 50 to 75%; balance is water.

16. The composition according to claim 15 wherein the gelling agent is one or more agents selected from the group consisting of agar, carrageenan, locust bean gum and alginic acid.

17. The composition of claim 15 wherein the inert oil is mineral oil.

18. The composition of claim 15, 16 or 17 wherein the therapeutic agent is theophylline, ampicillin or captopril.

19. A method of forming a non-compressed tablet having a network of multitudinous air holes and passages therein, and a density of less than one and capable of floating on gastric fluid vivo which comprises:
(1) forming a solution of a gelling agent in water, (2) forming a first mixture containing a therapeutic agent and a therapeutically acceptable inert oil, (3) cooling said solution, but not to the point where gelation takes place, (4) combining the solution and the first mixture to produce a second mixture containing from 0.5 to 2%
of gelling agent; 5 to 30% of oil; 25 to 50% of therapeutic agent and the balance water, all amounts by weight based on the total weight, (5) pouring the second mixture into a tablet mold and letting it stand in the mold to form a gel, and (6) drying the molded gel tablet to reduce the water content.

20. The method according to claim 19 wherein the gelling agent is one or more agents selected from the group consisting of agar, carrageenan, locust bean gum and alginic acid.

21. The method according to claim 19 or 20 wherein the therapeutic agent is theophylline, ampicillin or captopril.

22. A tablet composition obtainable from an aqueous mixture containing 6 parts of theophylline, 2 parts of mine-ral oil, 0.2 part agar and 10 parts water, said mixture being subjected to gelling and drying.

23. A tablet composition obtainable from an aqueous mixture containing 6 parts of theophylline, 0.3 part of iota carrageenan, 2 parts of mineral oil and 10 parts of water, said mixture being subjected to gelling and drying.

24. A tablet composition obtainable from an aqueous mixture containing 6 parts of theophylline, 0.3 part of kappa carrageenan, 2 parts of mineral oil and 10 parts of water, said mixture being subjected to gelling and drying.

25. A tablet composition obtainable from an aqueous mixture containing 6 parts of theophylline, 0.1 part of kappa carrageenan, 0.1 part of locust bean gum, 2 parts of mineral oil and 10 parts of water, said mixture being subjected to gelling and drying.

26. A tablet composition obtainable from an aqueous mixture containing 6 parts of theophylline, 0.2 part of iota carrageenan, 0.1 part of locust bean gum, 2 parts of mineral oil and 10 parts of water, said mixture being subjected to gelling and drying.

27. A tablet composition obtainable from an aqueous mixture containing 6 parts of theophylline, 0.2 part of alginic acid, 0.1 part of locust bean gum, 2 parts of mineral oil and 10 parts of water, said mixture being subjected to gelling and drying.

28. A tablet composition obtainable from an aqueous mixture containing 90 parts of anhydrous ampicillin, 16 parts of mineral oil, 3.2 parts of agar, 8 parts of sodium citrate and 160 parts of water, said mixture being subjected to gelling and drying.

29. A tablet composition obtainable from an aqueous mixture containing 6 parts of anhydrous ampicillin, 2 parts of mineral oil, 0.2 part of agar, 0.5 part of sodium citrate and 10 parts of water, said mixture being subjected to gelling and drying.

30. A tablet composition obtainable from an aqueous mixture containing 7 parts of captopril, 1 part of mineral oil, 0.2 part of agar, 1 part of lactose, 0.3 part of cal-cium gluconate and 10 parts of water, said mixture being subjected to gelling and drying.

31. A tablet composition obtainable from an aqueous mixture containing 7 parts of captopril, 2 parts of mineral oil, 0.3 part of agar and 10 parts of water, said mixture being subjected to gelling and drying.