WO1986006627A1

WO1986006627A1 - Sustained release theophylline compositions and processes

Info

Publication number: WO1986006627A1
Application number: PCT/US1986/001025
Authority: WO
Inventors: Phillip G. Osborn
Original assignee: Riker Laboratories Inc
Current assignee: Riker Laboratories Inc
Priority date: 1985-05-15
Filing date: 1986-05-15
Publication date: 1986-11-20
Anticipated expiration: 1987-11-15
Also published as: EP0222883A1

Abstract

Sustained-release theophylline products comprising theophylline in an amount of about 85 to 98% by weight and guar gum in an amount of about 2 to 15% by weight. Processes for preparaing such compositions and pharmacological methods for using such compositions are also disclosed.

Description

^'"SUSTAINED RELEASE THEOPHYLLINE COMPOSITIONS AND PROCESSES'

TECHNICAL FIELD

.This invention relates to theophylline sustained-release compositions, processes for preparing strøh compositions and pharmacological methods for using such compositions.

BACKGROUND OF THE INVENTION

There are applications for theophylline sustained-release tablets having a high concentration of theophylline (about 85% or greater by weight of theophylline) and a sustained-release profile of. theophylline for between 6 and 24 hours. For example, for a prescribed dosage of theophylline,. fewer tablets overall and per 24 hour period have to be consumed and less sustained-release agent is required per tablet. Another advantage is the tablet size can be smaller.

There are also applications for theophylline sustained-release tablets in which the rate of release of theophylline is substantially unaffected by the acidity or alkalinity of the releasing medium. Individuals have different internal acidity levels, in particular in the stomach, and this can cause variations in the sustained-release rate if it is pH dependent.

Substained-release theophylline products are known. For example, U. S. Patent No. 4,389,393 discloses sustained-release compositions which contain theophylline as the medicament and a high molecular weight hydroxypropyl ethyl cell ulose as the sustained-release agent. This patent generally discloses that the hydroxypropylmethylcell ulose may be present in an amount of 5 to about 30% weight.

Further, U. S. Patent No. 4,264,573 discloses sustained-release compositions which comprise 30 to 90? by weight of a medicament and one or more excipients such as a binder. The medicament may be theophylline. A wet granulation process is disclosed for preparing these sustained-release products.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a novel theophylline sustained-release composition comprising about 85-98% by weight of theophylline and about 2-15 by weight of guar gum, the composition being prepared by granulating a mixture of the theophylline (in particulate form) and the guar gum in the presence of water as a granulating liquid, and substantially drying the mixture. This composition may, for example, then be manufactured into a sustained-release tablet.

The present invention also provides a process for preparing a theophylline sustained-release composition comprising the steps of a) granulating a mixture comprising about 85-98 parts by weight of theophylline (in particulate form) and about 2-15 parts by weight of guar gum in the presence of water as a granulating liquid, and b) substantially drying the mixture.

The theophylline sustained-release compositions of the present invention desirably comprise a high percentage of theophylline and provide a desirable profile of susta ned-release of theophylline when incorporated in tablet form. Further, desirably the sustained-release rate of theophylline from such tablets is not signif cantly affected by the acidity or alkalinity of solutions which simulate the different acidity or alkalinity expected within the normal range of pH in a human gastrointestinal system. Other advantages are that the rate of release and period of release of theophylline can be controlled in the instant compositions by varying the proportion of theophylline to guar gum. Further, the theophylline sustained-release compositions may be manufactured using conventional equipment and can be manufactured into tablets using conventional tabletting equipment.

DETAILED DESCRIPTION OF THE INVENTION

The theophylline sustained-release compositions of the present invention comprise about 85-98% by weight, preferably about 90-98% by weight, and most preferably about 95% by weight of theophylline. As for the guar gum which acts as the sustained-release agent, it is present in the theophylline sustained-release compositions of the invention in an amount of about 2-15% by wei ght, . preferably about 2-10% by weight and most preferably about 5% by weight. By "guar gum" as used in the instant specifications and claims is meant that material so specified in the USP XXI NF XVI. Guar gum^' is the ground endosperm of the plant Cyamopsis tetragonul obus (Linnέ).

The theophylline sustained-release compositions of the present invention are prepared by granulating a mixture of theophylline (in particulate form), guar gum and water as a granulating liquid, and thereafter substantially drying the mixture. By "particulate form" is meant that the majority of the theophylline particles are in the range of about 20 to 500 micrometers in diameter. By "substantially drying" is meant that the level of water in the dried mixture is less than about 2% (weight/weight). Preferably, the water content is between 0% and 0.5% (weig t/weight).

As for the processes of the present invention for preparing the theophylline sustained-release compositions, a conventional granulating device may be used. The preferred drying step involves the use of a fluid bed -4- dryer .

A preferred process of the present invention comprises the following steps. Theophylline is prescreened through an appropriate mesh screen to provide particles of the desired size. Such theophylline is then granulated with guar gum in the presence of water as the granulating liqu_.id, the water being added by spraying. Thereafter, the theophyl 1 i ne-guar gum mixture is screened either in the wet state or dry state to provide particles of tftfe descri bed size. If the mixture is screened in the wet-state, it is thereafter dried.

While, as noted above, theophylline and guar gum are first granulated in the presence of water and then dried, the compositions of the invention may be prepared using and the processes of the invention may involve a simultaneous granulation and drying procedures.

While not wishing to be bound to any particular theory, it is believed that the desired sustained-release characteristics of the instant compositions result from the formation of a film of guar gum around the theophylline particles. Formation of such a film is believed to result from hydration of the guar gum and the coating of theophylline particles with hydrated guar gum during the wet granulation process. In manufacturing tablets comprising the theophylline sustained-release compositions of the invention, acceptable pharmaceutical compression lubricants such as magnesium stearate, stearic acid, zinc stearate, the hydrogenated vegetable oil which is available under the trade s_ designation Sterotex from Capital City Products, USA, or other like lubricants may desirably be employed.

Preferred embodiments of this invention are described by way of Example. EXAMPLE 1

Theophylline compositions containing about 2%, about 4.8%, about 9.1% and about 16.6% of guar gum by weight were prepared as follows. 1kg of theophylline was screened through a 20 mesh screen and placed in a planetary mixing device. Powdered guar gum (Supercol U from Polypro International Inc. (USA)), in one of the amounts indicated in Table 1, was added to the theophylline and the combination blended to provide a uniform mixture. Water, in the amount specified in Table 1 for the amount of guar gum used, was then added by spraying at a rate of 1.5 liters/hour into the mixture while mixing to maintain a homogeneous granulation.

TABLE 1

Guar gum (g) Volume of Water (ml )

0 170

20 460

50 550

100 700 200 900

The wet granules so formed were then dried at 60 for 24 hours to a moisture content of 0.4% and were subsequently dry-screened through a 16 mesh screen. 1kg of the dry-screened mixture was blended with lg of magnesium stearate and the blended mixture was converted into

3/8-inch diameter biconvex tablets using a single punch rotary tabletting machine.

For each of the above tabletted compositions, the release of theophylline versus time was determined by dissolution tests conducted as follows: A USP XXI dissolution apparatus (paddle) was employed. The medium used was 875 ml of 0.1M hydrochloric acid, containing 0.05% by weight of polysorbate 80. Forty-five minutes into the procedure there was added to the medium dibasic potassium phosphate as a solid in an amount of 6. lg. At 90 minutes, • the pH was titrated to a pH of 7.5 with a solution of sodium hydroxide. Mean values of theophylline released (expressed as a percentage of theophylline in a tablet) 'for 6 tablets of each of the above-prepared compositions are included in Table 2.

TABLE 2

% guar gum Theophyl! ine Theophyl line released after released after 6 hours 12 hours

02 . 100% 100%

0 . 2% 75.8% 98.7%

4 . 8% 42.3% 67.2%

9 . 1 % 32.1% 51.5%

1 166..6 6%% 28.3% 43.8%

E X AMP L E 2 >

Four kg of anhydrous theophylline was screened through a 20 mesh screen. The sieved theophylline was then blended o with 0.20 kg of Supercol U (guar gum; available from

Polypro International Inc.) in a "Diosna V25" high speed mi xer/granulator (available from Dierks and Sohne, West Germany) for two minutes at low speed. While mixing was continued, 1870 ml of water was added to the mixture at a rate of 500 ml per minute as a fine spray. Mixing was continued for an additional 2 minutes at low speed. Granulation was completed by mixing for 30 seconds at high speed with the chopping blade on. After waiting 30 minutes from the first addition of water, the wet granulate was dried in a fluid bed dryer with an inlet temperature of 60°C. and a final outlet temperature of 35°C. (loss on drying of granules of 0.4%). The dry granulate was screened through a 16 mesh screen. Tabletting was accomplished as follows. One-tenth kg ^'-of dried and screened granulate from above was hand mixed with 0.001 kg of magnesium stearate in a plastic bag. The resulting mixture was blended with a further 0.9 kg of dried and screened theophylline granulate in a cube blender for 15 minutes. Tablets containing 250 mg of theophylline were then manufactured using a single punch rotary machine using 3/8" biconcave punches.

Claims

WHAT IS CLAIMED IS:

1. A theophylline sustained-release composition comprising about 85-98% by weight of theophylline and about 2-15% by weight of guar gum, said composition being prepared by granulating a mixture of said theophylline in particulate form, said guar gum and water as a granulating liquid, and substantially drying said mixture.

2. A theophylline sustained-release composition according to Claim 1, wherein said composition comprises about 90-98% by weight of theophylline and about 2-10% by weight of guar gum.

3. A theophylline sustained-release composition according to Claim 1, wherein said composition comprises about 95% by weight of theophylline and about 5% by weight of guar gum.

4. A theophylline sustained-release tablet comprising theophylline sustained-release composition of Claim 1.

5. A process for preparing a theophylline sustained-release composition comprising the steps of a) granulating a mixture comprising about 85-98 parts by weight of theophylline in particulate form and about 2-15 parts by weight of guar gum in the presence of water as a granulating liqui , and b) substantially drying said mixture.

6. A process according to Claim 5, further comprising the step of screening the dried mixture from step b) to provide particles of the desired particle size.

7. A method for inducing bronchodi lation in a mammal comprising administering orally to said mammal a composition according to Claim 1 in an amount sufficient to induce bronchodi lati on.