CONTROLLED RELEASE PREPARATIONS

Abstract

Controlled release preparations and soft capsules are provided. Also provided are emulsions and suspensions, including compositions and methods of manufacturing controlled release soft capsules, where the fill contains a suspension and/or an emulsion.

Claims

1. A controlled release soft capsule having a shell and a matrix fill comprising an active ingredient or drug, wherein the matrix fill consists of two phases in the form of an emulsion, wherein the emulsion comprises a hydrophilic internal phase consisting essentially of polyethylene glycol of molecular weight ranging from about 200 to about 8000, methyl cellulose and an active ingredient or drug and a lipid or lipophilic external phase; and wherein the ratio of the internal phase to external phase is from about 0.5:10 to about 1:1 by weight.

2. The controlled release soft capsule of claim 1, wherein the external phase comprises a vegetable oil, hydrogenated vegetable oil, fatty acid, wax, fatty acid ester, or a combination thereof.

3. The controlled release soft capsule of claim 1, wherein the internal phase is structured.

4. The controlled release soft capsule of claim 3, wherein the internal phase is solid, semi-solid or gel.

5. The controlled release soft capsule of claim 1, wherein the active ingredient or drug is dispersed in the internal phase as a solution or suspension form.

6. The controlled release soft capsule of claim 1, wherein the ratio of internal phase to external phase is from 1:9 to 1:1 by weight.

7. The controlled release soft capsule of claim 1, wherein the ratio of the active ingredient or drug to the matrix fill is from about 1:100 to about 1:2 by weight.

8. The controlled release soft capsule of claim 1, wherein the emulsion comprises a surfactant or combination of surfactants having HLB values ranging from about 2 to about 20.

9. The controlled release soft capsule of claim 1, wherein the active ingredient or drug is distributed in both an external and internal phase.

10. The controlled release soft capsule of claim 9, wherein the active ingredient or drug is in the form of solid particles.

11. The controlled release soft capsule of claim 1, wherein the active ingredient or drug is selected from the group consisting of anti-asthmatics, narcotic analgesics, narcotic antagonists, and cardiovascular drugs and/or is selected from the group consisting of diltiazem, nifedipine, oxycodone, morphine, morphine analogues, and morphine antagonists.

12. A method of manufacturing a controlled release soft capsule according to claim 1, the method comprising: (a) dispersing the active ingredient or drug in an internal phase to form a clear solution or suspension using a propeller or homogenizer mixer; (b) adding the internal phase to a molten external phase containing at least one surfactant in an amount from about 0.1% to about 5% by weight to form a resulting mixture; (c) forming an emulsion from the resulting mixture by subjecting the mixture to mechanical forces generated by a propeller mixer, a homogenizer, or a microfluidizer; (d) cooling the emulsion to from about 20° C. to about 35° C.; and (e) encapsulating the emulsion using a rotary die encapsulation machine to form the controlled release capsule.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0024] Generally, the controlled release soft capsules according to the invention comprise a shell and a matrix fill. The matrix fill can be a suspension-type matrix or an emulsion-type matrix.

[0025] In an embodiment of the invention having a suspension-type matrix fill, the active ingredient or drug is incorporated in the matrix fill as solid particles in lipid or lipophilic materials such as vegetable oils, hydrogenated vegetable oils, silicon oils, fatty acids, waxes, or fatty acid esters, or a combination thereof. The matrix composition may further contain a release regulator to modify the release profile to suit an optimum therapeutic requirement. The release regulator can be a surface-active agent that enhances water penetration into the lipid or lipophilic matrix to increase drug release. Examples of release regulators are fatty acid slats, fatty acid esters, or fatty acid polyoxyethylene derivatives. Surfactants having HLB values between about 3 and about 40 can be selected as release regulators.

[0026] In another embodiment of the invention having a suspension-type matrix fill, the matrix, at room or body temperature, can be in a fluid or structured solid state (solid, semi-solid, or gel). The drug can be partially soluble in the matrix while the rest of the drug is in a solid form. The presence of drug in two physical forms, solid particles and solution, can be useful by providing dual release patterns where one drug state is released faster than the other form.

[0027] In addition to suspension-type matrix fills, the invention also includes emulsion-type fills. Such fills are described herein as “emulsion-type” fills because they comprise an emulsion. The matrix fills for these embodiments can be characterized generally as emulsion-type fills, even though the active ingredient or drug can be present as a suspension in one or more phases of the emulsions of embodiments as described herein.

[0028] In another embodiment of the invention, the soft gel matrix fill comprises two phases in the form of an emulsion (emulsion-type matrix). The emulsion can be a water-in-oil type emulsion. The internal phase comprises aqueous or hydrophilic materials, such as polyethylene glycol of molecular weight ranging from about 200 to about 8000. The internal phase can also be an aqueous or hydro-alcoholic solution comprising cellulose derivatives, polyacrylates, or polyvinyl polymers. Examples of such polymers include methylcellulose, hydroxypropylmethyl cellulose, polymethylmethacrylate, and polyvinylpyrrolidone (PVP). The internal phase state can be “fluid” or “structured.” A “fluid” internal phase, as used herein, means a completely flowable liquid whose globules can aggregate to make a larger globule. A “structured” internal phase, as used herein, means a solid, semisolid or a gel whose shape is relatively stable and does not usually aggregate to form a large globule. A structured internal phase therefore provides more controlled drug release and stabilizes the physical state of the matrix.

[0029] The external phase of the matrix fill emulsion comprises lipid or lipophilic materials similar to those described above. The active ingredient or drug can be dispersed in the internal phase as a solution and/or as a suspension. The emulsion matrix can contain a surfactant or combination of surfactants having HLB values ranging from about 2 to about 20. The HLB range can also be from about 5 to about 15.

[0030] In another embodiment, the matrix fill is of an emulsion type, where the drug is distributed in both external and internal phases. One portion of the active ingredient or drug in form of solid particles can be incorporated in the internal phase, while another portion is dispersed in the external phase as solid particles.

[0031] This invention also provides methods for making controlled release products in a soft capsule form. The methods are applicable for production of controlled release preparations of low dose (potent) drugs that are highly water-soluble. The methods are also suitable for preparing controlled release products of relatively less potent, moderately water-soluble drugs.

[0032] The suspension-type matrix fill compositions can be used for drugs that are moderately water-soluble at a dosage of between about 25 mg to about 500 mg. Such drugs include non-steroid anti-inflammatory drugs and anti-asthmatics, e.g., diclofenac, naproxene, ibuprofen, ketoprofen, celecoxib, and theophylline.

[0033] On the other hand, the emulsion-type matrix fill can be used for highly water-soluble molecules such as anti-asthmatics, narcotic analgesics, and analgesic antagonists as well as cardiovascular drugs, e.g., diltiazem, nifidipine, oxycodone, morphine, morphine analogues, and morphine antagonists.

[0034] The suspension-type matrix fill can be manufactured by mixing the active ingredient or drug with the lipid or lipophilic matrix ingredients using mechanical or ultrasonic forces. Applying heat while or prior to mixing has the benefit of reducing the matrix viscosity. Reduced matrix viscosity in turn results in more efficient mixing. The matrix materials can be heated to temperature at or close to the melting point of the matrix composite. The melting point of the composite matrix is workable in the range of from about 25° C. to about 70° C. The melting point range of the matrix composition can also be from about 30° C. to about 50° C. The drug-to-matrix ratio can be concentrated enough to provide a low total mass per unit dose, yet can still be flowable to allow encapsulation using a rotary die encapsulation machine. A workable drug-to-matrix ratio range is from about 1:9 to about 1:1 by weight. The drug-to-matrix ratio range can also be from about 1:8 to about 1:1 by weight.

[0035] The emulsion-type of matrix fill can be manufactured by dispersing the active ingredient or drug in the internal phase to provide a clear solution or suspension. The active ingredient or drug can be dispersed using propeller or homogenizer mixers. The internal phase materials can then be added to the molten external phase containing surfactant from about 0.1% to about 5% by weight. The emulsion can be made using mechanical forces generated by a propeller mixer, a homogenizer, or a microfluidizer. The matrix is then cooled to a temperature of from about 20° C. to about 35° C. for encapsulation using a rotary die encapsulation machine. The internal-to-external phase workable ratio is in the range of from about 0.5:10 to about 1:1 by weight. The ratio range can also be from about 1:9 to about 1:1 by weight. The workable drug-to-matrix ratio can be from about 1:100 to about 1:2 by weight. The range of the drug-to-matrix can also be from about 1:50 to about 1:3 by weight.

[0036] The following Examples are intended for purposes of illustration only, and should not be interpreted as limiting in any way of the scope of the invention.

EXAMPLES

Formulation 1:

[0037]

TABLE-US-00001 Ingredient Amount (% w/w) Diltiazem Hydrochloride 5.00 Soybean Oil 6.24 Vegetable Shortening 60.00 Vegetable Flakes 12.00 Glyceryl mono oleate 2.35 Span 60* 0.16 Methyl Cellulose 1.50 PEG 3350 4.50 PEG 400 8.25 *sorbitan stearate.

Procedure:

[0038] Vegetable shortening, vegetable flakes, glyceryl mono oleate, Span 60 and soybean oil were melted together at 50° C. to 70° C. (wax or lipophilic phase). Methylcellulose, PEG 3350 and PEG 400 were melted separately at 50° C. to 70° C. (aqueous phase). Diltiazem hydrochloride was dispersed in the melted aqueous phase and added slowly to the wax phase with homogenization, while maintaining the temperature between 50° C. and 70° C. The resultant homogeneous emulsion phase was cooled and encapsulated.

Evaluation:

[0039] Filled capsules were subjected to dissolution as per USP using the paddle method in distilled water at 100 RPM. [0040] Result: T.sub.50 (time required for 50% dissolution) is about 18 h. [0041] Note: The Procedure and Evaluation followed for Formulation 1 was also used for Formulations 2-24 below.

Formulation 2:

[0042]

TABLE-US-00002 Ingredient Amount (% w/w) Diltiazem Hydrochloride 5.00 Soybean Oil 27.84 Vegetable Shortening 38.40 Vegetable Flakes 12.00 Glyceryl mono oleate 2.35 Span 60 0.16 Methyl Cellulose 1.50 PEG 3350 4.50 PEG 400 8.25 [0043] Result: T.sub.50 (time required for 50% dissolution) is about 3 h.

Formulation 3:

[0044]

TABLE-US-00003 Ingredient Amount (% w/w) Diltiazem Hydrochloride 5.00 Soybean Oil 23.84 Vegetable Shortening 42.40 Vegetable Flakes 12.00 Glyceryl mono oleate 2.35 Span 60 0.16 Methyl Cellulose 1.50 PEG 3350 4.50 PEG 400 8.25 [0045] Result: T.sub.50 (time required for 50% dissolution) is about 1 h.

Formulation 4:

[0046]

TABLE-US-00004 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 4.68 Vegetable Shortening 44.70 Vegetable Flakes 9.00 Glyceryl mono oleate 2.70 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 9.00 PEG 400 16.50 [0047] Result: T.sub.50 (time required for 50% dissolution) is about 4 h.

Formulation 5:

[0048]

TABLE-US-00005 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 20.88 Vegetable Shortening 25.50 Vegetable Flakes 12.00 Glyceryl mono oleate 2.70 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 9.00 PEG 400 16.50 [0049] Result: T.sub.50 (time required for 50% dissolution) is about 8 h.

Formulation 6:

[0050]

TABLE-US-00006 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 20.88 Vegetable Shortening 25.50 Vegetable Flakes 9.00 Glyceryl mono oleate 2.70 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 12.00 PEG 400 13.50 [0051] Result: T.sub.50 (time required for 50% dissolution) is about 3.5 h.

Formulation 7:

[0052]

TABLE-US-00007 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 27.00 Vegetable Shortening 13.88 Vegetable Flakes 18.00 Glyceryl mono oleate 2.70 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 9.00 PEG 400 16.50 [0053] Result: T.sub.50 (time required for 50% dissolution) is about 4 h.

Formulation 8:

[0054]

TABLE-US-00008 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 27.00 Vegetable Shortening 13.88 Vegetable Flakes 18.00 Glyceryl mono oleate 2.70 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 12.00 PEG 400 13.50 [0055] Result: T.sub.50 (time required for 50% dissolution) is about 11 h.

Formulation 9:

[0056]

TABLE-US-00009 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 23.38 Vegetable Shortening 24.00 Yellow Beeswax 6.00 Vegetable Flakes 6.00 Glyceryl mono oleate 2.70 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 9.00 PEG 400 16.50 [0057] Result: T.sub.50 (time required for 50% dissolution) is about 10 h.

Formulation 10:

[0058]

TABLE-US-00010 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 18.65 Vegetable Shortening 20.00 Yellow Beeswax 5.00 Vegetable Flakes 5.00 Glyceryl mono oleate 3.00 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 9.00 PEG 400 16.50 [0059] Result: T.sub.50 (time required for 50% dissolution) is about 3.5 h.

Formulation 11:

[0060]

TABLE-US-00011 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 23.38 Vegetable Shortening 24.00 Yellow Beeswax 6.00 Vegetable Flakes 6.00 Glyceryl mono oleate 2.70 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 15.00 PEG 400 10.50 [0061] Result: T.sub.50 (time required for 50% dissolution) is about >24 h.

Formulation 12:

[0062]

TABLE-US-00012 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 18.65 Vegetable Shortening 20.00 Yellow Beeswax 5.00 Vegetable Flakes 5.00 Glyceryl mono oleate 3.00 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 15.00 PEG 400 10.50 [0063] Result: T.sub.50 (time required for 50% dissolution) is about >24 h.

Formulation 13:

[0064]

TABLE-US-00013 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 10.39 Vegetable Shortening 31.99 Yellow Beeswax 8.00 Vegetable Flakes 8.00 Glyceryl mono oleate 2.70 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 9.00 PEG 400 16.50 [0065] Result: T.sub.50 (time required for 50% dissolution) is about 6.5 h.

Formulation 14:

[0066]

TABLE-US-00014 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 8.66 Vegetable Shortening 26.67 Yellow Beeswax 6.67 Vegetable Flakes 6.67 Glyceryl mono oleate 3.00 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 4.00 PEG 3350 12.00 PEG 400 22.00 [0067] Result: T.sub.50 (time required for 50% dissolution) is about 3.5 h.

Formulation 15:

[0068]

TABLE-US-00015 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 10.34 Vegetable Shortening 32.00 Yellow Beeswax 8.00 Vegetable Flakes 8.00 Glyceryl mono oleate 3.00 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 15.00 PEG 400 10.50 [0069] Result: T.sub.50 (time required for 50% dissolution) is about >24 h.

Formulation 16:

[0070]

TABLE-US-00016 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 8.66 Vegetable Shortening 26.67 Yellow Beeswax 6.67 Vegetable Flakes 6.67 Glyceryl mono oleate 3.00 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 4.00 PEG 3350 20.00 PEG 400 14.00 [0071] Result: T.sub.50 (time required for 50% dissolution) is about 6.5 h.

Formulation 17:

[0072]

TABLE-US-00017 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 46.34 Vegetable Shortening 8.00 Yellow Beeswax 2.00 Vegetable Flakes 2.00 Glyceryl mono oleate 2.70 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 15.00 PEG 400 10.50 [0073] Result: T.sub.50 (time required for 50% dissolution) is about 1.5 h.

Formulation 18:

[0074]

TABLE-US-00018 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 38.66 Vegetable Shortening 6.67 Yellow Beeswax 1.67 Vegetable Flakes 3.00 Glyceryl mono oleate 3.00 Span 60 0.12 Lecithin 0.25 Methyl Cellulose 4.00 PEG 3350 20.00 PEG 400 14.00 [0075] Result: T.sub.50 (time required for 50% dissolution) is about 1.5 h.

Formulation 19:

[0076]

TABLE-US-00019 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 34.34 Vegetable Shortening 16.00 Yellow Beeswax 4.00 Vegetable Flakes 4.00 Glyceryl mono oleate 2.70 Span 60 0.12 Lecithin 0.30 Methyl Cellulose 3.00 PEG 3350 15.00 PEG 400 10.50 [0077] Result: T.sub.50 (time required for 50% dissolution) is about 20 h.

Formulation 20:

[0078]

TABLE-US-00020 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.00 Soybean Oil 28.66 Vegetable Shortening 13.33 Yellow Beeswax 3.33 Vegetable Flakes 3.33 Glyceryl mono oleate 3.00 Span 60 0.12 Lecithin 0.25 Methyl Cellulose 4.00 PEG 3350 20.00 PEG 400 14.00 [0079] Result: T.sub.50 (time required for 50% dissolution) is about 20 h.

Formulation 21:

[0080]

TABLE-US-00021 Ingredient Amount (% w/w) Diltiazem Hydrochloride 5.00 Soybean Oil 12.46 Vegetable Shortening 52.50 Vegetable Flakes 3.50 Glyceryl mono oleate 2.65 Span 60 0.20 Methyl Cellulose 2.50 PEG 900 15.75 PEG 400 10.50 [0081] Result: T.sub.50 (time required for 50% dissolution) is about 0.3 h.

Formulation 22:

[0082]

TABLE-US-00022 Ingredient Amount (% w/w) Diltiazem Hydrochloride 5.00 Soybean Oil 9.79 Vegetable Shortening 27.50 Vegetable Flakes 2.75 Glyceryl mono oleate 2.75 Glyceryl mono stearate 2.00 Span 60 1.00 Methyl Cellulose 4.00 PEG 900 8.4 PEG 400 25.20 [0083] Result: T.sub.50 (time required for 50% dissolution) is about 0.3 h.

Formulation 23:

[0084]

TABLE-US-00023 Ingredient Amount (% w/w) Famotidine 1.00 Soybean Oil 12.00 Vegetable Shortening 15.00 Vegetable Flakes 1.50 Glyceryl mono oleate 1.50 Span 60 0.06 Methyl Cellulose 6.90 Cremophor RH 40 0.69 Glyceryl mono stearate 3.45 PEG 400 57.96 [0085] Result: T.sub.50 (time required for 50% dissolution) is about 0.6 h.

Formulation 24:

[0086]

TABLE-US-00024 Ingredient Amount (% w/w) Vegetable Shortening 25.00 Methyl Cellulose 11.30 Cremophor RH 40 0.70 Glyceryl mono stearate 3.45 PEG 400 59.50

Formulation 25 (Dual Release):

[0087]

TABLE-US-00025 Ingredient Amount (% w/w) Diltiazem Hydrochloride 10.33 Soybean Oil 36.15 Vegetable Shortening 10.74 Yellow Beeswax 2.69 Vegetable Flakes 2.69 Glyceryl mono oleate 2.87 Span 60 0.11 Lecithin 0.27 Methyl Cellulose 3.60 PEG 3350 17.98 PEG 400 12.59

Procedure:

[0088] Vegetable shortening, vegetable flakes, yellow beeswax, glyceryl mono oleate, lecithin, Span 60 and soybean oil were melted together at 50° C. to 70° C. (wax phase). Methylcellulose, PEG 3350 and PEG 400 were melted separately at 50° C. to 70° C. (aqueous phase). About 77% of diltiazem hydrochloride was dispersed in the melted aqueous phase and added slowly to the wax phase with homogenization, while maintaining the temperature between 50° C. and 70° C. Remaining 23% of diltiazem hydrochloride was added to the final resultant homogeneous emulsion. The emulsion was cooled and encapsulated.

Evaluation:

[0089] Filled capsules were subjected for dissolution as per USP using paddle method in distilled water at 100 RPM. [0090] Result: T.sub.50 (time required for 50% dissolution) is about 4.2 h.

Formulation 26:

[0091]

TABLE-US-00026 Ingredient Amount (% w/w) Oxycodone Hydrochloride 5.00 Soybean Oil 36.56 Vegetable Shortening 11.00 Yellow Beeswax 2.75 Vegetable Flakes 2.75 Glyceryl mono oleate 3.35 Span 60 0.55 Lecithin 0.28 Methyl Cellulose 4.00 PEG 3350 20.00 PEG 400 14.00 [0092] Procedure & Evaluation: Procedure adopted was as described in Formulation 1. [0093] Result: T.sub.50 (time required for 50% dissolution) is about 3.5 h.

Formulation 27:

[0094]

TABLE-US-00027 Ingredient Amount (% w/w) Oxycodone Hydrochloride 5.00 Water 6.00 Soybean Oil 36.56 Vegetable Shortening 11.00 Yellow Beeswax 2.75 Vegetable Flakes 2.75 Glyceryl mono oleate 3.10 Span 60 0.55 Lecithin 0.28 Methyl Cellulose 4.00 PEG 3350 20.00 PEG 400 8.00

Procedure:

[0095] Procedure adopted was similar to Formulation 25, but the model drug was dissolved in water before adding to the rest of the formulation.

Evaluation:

[0096] Filled capsules were subjected for dissolution as per USP using paddle method in distilled water at 100 RPM. [0097] Result: T.sub.50 (time required for 50% dissolution) is about >8 h.

Formulation 28:

[0098]

TABLE-US-00028 Ingredient Amount (% w/w) Theophylline 10.00 Soybean Oil 36.36 Vegetable Shortening 45.45 Vegetable Flakes 3.64 Glyceryl mono oleate 4.45 Cremophor EL 40 0.91

Procedure:

[0099] Vegetable shortening, vegetable flakes, GMO, and Cremophor EL 40 were melted with soybean oil between 50° C. and 70° C. To this melted mass, theophylline was added and homogenized. The resultant mixture was cooled while mixing and encapsulated. [0100] Result: T.sub.50 (time required for 50% dissolution) is about 1 h.

Formulation 29:

[0101]

TABLE-US-00029 Ingredient Amount (% w/w) Theophylline 10.00 Soybean Oil 36.36 Vegetable Shortening 45.45 Vegetable Flakes 4.32 Glyceryl mono oleate 4.45 Cremophor EL 40 0.23 [0102] Procedure: Procedure adopted was similar to Formulation 28. [0103] Result: T.sub.50 (time required for 50% dissolution) is about >24 h.

Formulation30:

[0104]

TABLE-US-00030 Ingredient Amount (% w/w) Theophylline 10.00 Soybean Oil 36.36 Vegetable Shortening 45.45 Vegetable Flakes 3.86 Glyceryl mono oleate 4.54 Cremophor EL 40 0.68 [0105] Procedure: Procedure adopted was similar to Formulation 28. [0106] Result: T.sub.50 (time required for 50% dissolution) is about 16 h.

Formulation 31:

[0107]

TABLE-US-00031 Ingredient Amount (% w/w) Theophylline 10.00 Soybean Oil 36.36 Vegetable Shortening 45.45 Vegetable Flakes 4.09 Glyceryl mono oleate 4.54 Cremophor EL 40 0.45 [0108] Procedure: Procedure adopted was similar to Formulation 28. [0109] Result: T.sub.50 (time required for 50% dissolution) is about 12 h.