Pharmaceutical Compositions of Deglycyrrhizinated Licorice (DGL)

This invention relates to a stable, novel formulation of the bitter-tasting deglycyrrhizinated licorice (DGL) which can be formulated to contain other ingredients known as pharmaceutical excipients that will enhance the dissolution and disintegration of the active ingredient, DGL, thereby making it unnecessary to chew tablets containing the DGL. These improved formulations can be swallowed and rapid and complete disintegration in the gastrointestinal tract can be achieved in order to release the ulcer-healing ingredient, DGL.

Licorice has been used for many years in the treatment of gastric disorders. In recent times the serious side effects of licorice became a major drawback to its use and in 1950 it was discovered that the constituent causing the major disturbance was glycyrrhizinic acid.

In the early 1950's it was decided to try and remove this ingredient and in 1952 a report appeared in Munchen Medizinische Wochenschrift by Dr. Irte that tablets of Caved-S were being used in treatment of peptic ulcers. This preparation (Caved-S) contained Bismuth Subnitrate (now known to be neurotoxic) and three other ingredients were used as flavoring or aromatic agents, Rhamni frangula cortex, Calami rhizoma and Foeniculi fructus. These latter two agents are described as being aromatic and irritants to the bowel. The DGL was prepared by a method which was described in Zagt U.S. Pat. No. 3,046,195.

Caved-S has the formulation:

This mixture is formulated as an uncoated tablet to be chewed and taken as 2 tablets on the average of 4 times per day. It is a dark brown, mottled tablet with the bitter taste of unsweetened licorice.

Several recent reports of studies using DGL indicated that the inclusion of antacids was not a necessary component to heal ulcers in laboratory animals and furthermore, that adequate dispersion of the DGL was necessary (capsules of DGL alone were not as effective clinically). In one study it was described that 7 patients out of 17 discontinued taking the medication because of the bitter taste of chewable tablets. In fact, the necessity of chewing 8 tablets a day is a real deterrent to patients taking the medication. It is a well-known fact that patient compliance drops dramatically with the increase in the number of tablets that have to be consumed. Several components of the current formulation, i.e. bismuth salts and aluminum compounds have recently been shown to have neurotoxic side effects.

Recent studies have demonstrated profound healing effects of DGL alone in rats who have aspirin (ASA), stress or restraint induced ulcers. Furthermore, in spite of recent clinical data demonstrating clinical effects of the current DGL formulation that are comparable to or better than cimetidine and ranitdine Caved-S sales have fallen over 90% in the last 5 years concurrent with the availability of tagamet, a product that is a tasteless tablet to be swallowed 4 times a day. In summary, because of a constellation of drawbacks, including drawbacks 1-4 listed below, the current formulation of DGL, while possessing reasonable clinical activity for treating peptic ulcers, is both a medical and marketing failure.

(1) There is a low quantity of active ingredient (DGL) per tablet, thereby necessitating a large (8) number of tablets to be taken daily.

(2) There is the presence of a large quantity of inactive ingredients per tablet, thereby making it impossible to adequately increase the amount of active ingredient and also there is a combination of many ingredients making it difficult to obtain FDA approval.

(3) The active ingredient is bitter and unpleasant in taste and must be chewed in order to disperse the DGL property. (4) Inert ingredients are present that are potentially harmful.

Because of the above defects there is a need for a novel formulation of DGL that is designed to overcome each of the drawbacks; thereby, producing a medically and commercially viable product taking advantage of the desirable properties of DGL in treating gastric ulcers, duodenal ulcers, and other forms of ulcers.

The present invention is directed to stable, oral forms of DGL that are pharmaceutically acceptable and overcome either all or most of the inherent drawbacks set forth as items 1 to 4 above of the current commercial form of DGL (Caved-S). These drawbacks are remedied in one single formulation according to the invention to provide DGL in an orally acceptable tablet form or they can be remedied singly or in combination, thus partially correcting the drawbacks of the current commercial product (Caved-S).

Unless otherwise indicated all parts and percentages are by weight.

The composition can consist essentially of or consist of the stated materials.

Thoroughly mix 1, 2, and 3 in a suitable mixer. Dissolve 4 in 5. With the mixer running slowly add the solution of 4 in 5 to the mixture of 1, 2, and 3. Mix until a uniform wetted mass is obtained and add an additional quantity of 5 if necessary. Place the wet granulation in a drying oven or fluid bed dryer and dry at 42.degree. C. for approximately 4 hours or until no residual alcohol is present. Pass the dried material through a suitable stainless steel screen (approximately 12 mesh Tyler) having connected therewith a milling machine for comminuting. Place the milled material in a suitable blender. Blend for 5 minutess. Stop the blending and add 6 and 7 and blend for an additional 2 minutes. Compress the tablets on a rotary tablet press using suitable tooling.

Other disintegrants can be used besides Explotab, such as Primogel (see explotab) or Avicel (microcrystalline cellulose) in the appropriate quantity (between 1-8% by wt. of explotabs and 5-15% of Avicel), as long as the same procedure specified here is utilized, i.e. there is included some of the disintegrant in the initial wet granulation preparation and there is included some of the disintegrant in the outer core of the granulation mass. The purpose of using this procedure is to produce a tablet that will release the active ingredient, DGL, in a particle size range that is nearly identical to the particle size of the input active ingredient (DGL) without having to chew the bitter tasting tablet. Other disintegrants like sodium alginate, clays and ion exchange resins in the appropriate amounts 2-5%, 5-10% and 0.5-5.0% respectively can be used.

Other pharmaceutically acceptable binders can be used in place of polyvinyl pyrrolidine, e.g. avicel, starch.

Other pharmaceutically acceptable lubricants can be used in place of magnesium stearate, e.g. stearic acid, talc, corn starch and hydrogenated vegetable oils.

Coated tablets are produced in order to mask the taste and color of the active ingredient and to make it easier for the patient to swallow. The taste must be masked for reasons of compliance of the patient in taking the medicine and the color masked for the purposes of making the tablet pharmaceutically acceptable and a second benefit is that it will allow for the production of a comparative placebo tablet.

The tablets are then coated with a thin film of protective material which will dissolve in the stomach or intestine. A typical formulation is given below:

The above formulation also is converted to a coated tablet using the same film coating system and procedure in Example 1.

The process of microencapsulation is also well known for overcoming the objections to taste and color in pharmaceutical preparations that have problems of taste and color. Because of this a formulation is proposed which would contain DGL formulated as beads, microencapsulated and suspended so that a suitable concentration can be obtained that will allow for the administration of DGL, as a tasteless or pleasant tasting liquid.

Because there is no need to employ the large amounts of excipients and the other materials present in Caved-S, it is possible to increase the dosage of DGL in each tablet. Consequently it is only necessary to administer 4 tablets (and in some cases only 3 tablets) per day rather than the 8 tablets per day required with Caved-S.