Title:  Non-aqueous colonic purgative formulations

United States Patent:  6,162,464

Assignee:  Inkine Pharmaceutical, Inc. (Blue Bell, PA)

Filed:  March 31, 1997

Orally administered colonic purgative formulations and methods of its use for effecting partial or complete purgation of the colon in mammals, the formulations consisting of non-aqueous admixtures of a purgative salt selected from the group consisting of Mg₃ (PO₄)₂, MgHPO₄, Mg(H₂ PO₄)₂, MgSO₄, MgCl₂, Na₂ SO₄, sodium tartrate, potassium tartrate, magnesium tartrate and mixtures, thereof, administered in tablet or capsule form in purgative effective concentrations. Preferred embodiments make use of at least one or more magnesium phosphate salts, more preferably dibasic magnesium phosphate; other preferred embodiments include the addition of binders, dispersants and buffers which do not adversely affect osmolality or effectiveness of the purgative formulations.

DETAILED DESCRIPTION OF THE INVENTION

The term "patient" is used throughout the specification to describe an animal, preferably a human, to whom treatment with the compositions according to the present invention is provided. For treatment of those conditions which are specific for a specific animal such as a human patient, the term patient refers to that specific animal. In most instances in the description of the present invention, the term "patient" will refer to human patients.

The term "salt" or "purgative salt" is used throughout the present application to describe one or more of the anhydrous compounds which find use in purgative products according to the present invention. Salts according to the present invention may be found in their anhydrous form or as in hydrated crystalline form (i.e., complexed or crystallized with one or more molecules of water). Purgative salts for use in the present invention include, for example, Mg₃ (PO₄)₂, MgHPO₄, Mg(H₂ PO₄)₂, MgSO₄, MgCl₂, Na₂ SO₄, sodium tartrate, potassium tartrate, magnesium tartrate, or mixtures, thereof. Preferred salts include the magnesium phosphate salts, with a particularly preferred salt being magnesium monohydrogen phosphate (dibasic magnesium phosphate) or a mixture of magnesium monohydrogen phosphate and magnesium dihydrogen phosphate salts. The magnesium phosphate salts are preferred for use in the present invention because of the dual effect which is produced by both the phosphate anion and the magnesium cation. As a result of this dual action, the magnesium phosphate salts may be utilized in the present invention in amounts which are considered "low dose", i.e. in an amount which is unexpectedly low based upon or compared to other salts, such as sodium phosphate salts which find use in anhydrous purgative formulations.

The term "purgative effective amount" or "purgative effective dosage" is used throughout the specification to describe the amount or concentration of purgative salts used in the present invention which is effective for producing a purgative effect, i.e., the elimination or evacuation from the intestines of its contents. In the case of the magnesium phosphate salts, these salts have unexpectedly been found to be advantageously employed in amounts which are significantly lower than for the sodium phosphate salts. The term "purgative active" is used to describe salts according to the present invention which exhibit biological or pharmacological activity in the form of purgative activity.

The term "anhydrous" is used throughout the specification describe the form in which the purgative salts according to the present invention are administered. Anhydrous formulations are those which essentially have excluded water from the formulations, except, in such instances where the salt is hydrated or otherwise complexed with small amounts of water.

The physiology of intestinal secretion and absorption is generally well known as reflected in the reported literature. While not being limited by way of theory, Applicant's invention is believed to function by creating an increase in intra-luminal fluid of the small bowel to a significant degree and/or creating favorable osmotic conditions in the intestine which allows for a net secretion of sodium and water into the lumen. In addition, in certain embodiments which utilize magnesium phosphate anions, the osmotic effect of the phosphate anions in combination with the motility enhancing effect of the magnesium cations create a synergistic purgative effect which makes the magnesium phosphate salts particularly preferred for use in the present invention. This allows for tremendous fluxes of water to be present within the gastrointestinal lumen which exhibits increased motility, thus producing an unexpectedly effective purgative effect.

In producing formulations according to the present invention, in a preferred embodiment, the present invention consists of a dry admixture of dibasic magesium phosphate or a mixture of monobasic and dibasis magnesium phosphate in an anhydrous state. Formulations according to the present invention may be prepared by placing one or more of the purgative salts according to the present invention, in pharmaceutical form, in a ribbon blender or other similar mung apparatus to effect complete mixing of the components. Additional constituents such as tablet binders, dispersants and/or buffering agents in the range of approximately 0.025% to 25% by weight, more preferably about 1% to 5% by weight, may also be included in the admixture. The formulations may be formulated in tablet or capsule form for oral delivery to a patient.

In preferred embodiments according to the present invention, phosphate salts are used, preferably magnesium phosphate salts and more preferably magnesium monohydrogen phosphate or mixtures of magnesium monohydrogen phosphate and magnesium dihydrogen phosphate. In other preferred embodiments, the amount of magnesium dihydrogen phosphate may be substantially reduced or eliminated in its entirety. In these formulations, dibasic phosphate or tribasic phosphate salts such as magnesium dibasic phosphate and magnesium tribasic phosphate may be used alone or in combination as the principal or exclusive form of phosphate in the formulation, while maintaining a complete purgative effect. Other phosphate salts according to the present invention may also be used, but these salts are less preferred. Upon ingestion, phosphate salts cause a tremendous amount of water to be drawn into the gut. This influx of water causes an increase in intraluminal pressure, which in turn exerts a mechanical stimulus causing an increase in intestinal motility. The purgative effect of the phosphate salts appears to be proportionately related to the increase in the anionic state of the phosphate salt and may be differentiated in their mode of action from other salt formulations which are capable of producing a limited cathartic effect. One such salt, magnesium sulfate, for example, exerts its effect via the magnesium cation which causes hypermotility of the gut. Although not being limited by way of theory, it is believed that the magnesium phosphate salts according to the present invention exert their unexpected enhanced activity by virtue of the combined activity of the phosphate anion and magnesium cation, creating a dual effect.

The admixture of the present invention is formed into an easily administered dosage form, such as tablets or into capsules by methods well known in the art. As used herein, the term admixture refers to a formulation which includes at least one purgative salt, preferably a phosphate or magnesium salt, more preferably at least one magnesium phosphate salt and even more preferably magnesium hydrogen phosphate (alone or in combination with another purgative salt, preferably a magnesium phosphate salt) and at least one other component including other phosphate salts or other additives as disclosed herein. When forming tablets containing the purgative formulation, it will be appreciated that the salts can be compressed into a uniform mixture and can optionally include inert diluents such as a tablet binder. Preferably, the tablet binder is a pharmaceutically acceptable binder and is one which produces no appreciable osmotic effects. Examples of useful binders include non-ionic detergents from the Pluronic.TM. series, such as Pluronic F-68 (a trademark of BASF-Wyandotte Chemicals, defined as a condensate of ethylene oxide with a condensate of propylene oxide and propylene glycol), related non-ionic surfactants, and mechanical adhesives such as polyvinyl alcohol and sodium carboxymethylcellulose, among numerous others. Microcrystalline cellulose (MCC) may also be used to enhance the compactability of the purgative salts into the tablet or capsule form. One of ordinary skill may readily modify the additives combined with the purgative salts according to the present invention in order to optimize the formulations for oral delivery.

In another preferred embodiment of the instant invention, the tablet or capsules may also include inert dispersal agents which will facilitate dissolution of the tablet or capsule contents in the stomach of the patient. Preferably, the dispersal agent is a pharmaceutically acceptable dispersant and is one which also produces no appreciable osmotic effects. Examples of acceptable dispersants include microcrystalline cellulose (which is also useful as a compacting agent) and anhydrous lactose. A preferred dispersal agent is AC-DI-SOL, a cross-linked starch.

In another preferred embodiment of the present invention, the preferred composition may also include a buffering agent to minimize any acid imbalance which may accompany ingestion of the purgative formulation of Applicants' invention. Suitable buffering agents include magnesium hydroxide, aluminum hydroxide, calcium carbonate and magnesium carbonate.

An important characteristic of the colonic purgative formulations of the instant invention is that they function effectively as purgatives when administered in low volume dosages, as compared to known formulations. In this manner, 2 to 12 tablets, and preferably 4 to 10 tablets per dose, depending on tablet size and weight, with only fluids necessary to assist in swallowing the tablets, will provide complete purgation. The dosage may be administered in a single application but may be preferably administered in two applications separated by approximately 2 to 4 hours. Use of the formulations of this invention in tablet form effectively removes the colonic contents without requiring injection of large quantities of water. Conventional purgative products historically and currently available on the market have had to employ much greater liquid volumes in order to obtain the desired result.

The foregoing description is illustrative of the preferred embodiments shown. It is not intended to limit the present invention to the specific formulations shown and described, but instead it will be appreciated that adaptations and modifications will become apparent from the present disclosure and are intended to be within the scope of the claims.

Claim 1 of 25 Claims

What we claim is:

1. An orally administerable composition in a solid dosage form capable of inducing purgation of the colon of a patient comprising a colonic purgative effective amount of a nonaqueous admixture of a salt selected from the group consisting of Mg₃ (PO₄)₂, MgHPO₄, Mg(H₂ PO₄)₂, MgSO₄, MgCl₂, Na₂ SO₄, sodium tartrate potassium tartrate, magnesium tartrate and mixtures, thereof, and wherein the purgation of the colon is sufficient to prepare the colon for a surgical or diagnostic procedure, wherein the composition in a solid dosage form can be administered directly to a patient in nonaqueous form.

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