Title:  Solvent system for enhancing solubility

United States Patent:  6,383,515

Appl. No.:  322819

A pharmaceutically acceptable solution with a medicament suitable for filling a soft gelatin capsule is made from a solvent. The solvent contains a polymer, such as polyethylene glycol, and an acid salt of a compound having 3 or more carbon atoms, and a salt such as sodium propionate. The solvent may optionally contain a cosolvent, such as dimethyl isosorbide. The medicament may preferably comprise an analgesic such as aspirin or naproxen.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

We will now describe the preferred embodiments of the invention.

The formulation of the invention comprises three types of systems: (a) a solvent system; (b) a solvent system and a medicament; and (c) a solvent system, at least one medicament dissolved in the solvent system, and a softgel surrounding the medicament and solvent system.

The solvent system of the invention comprises a low molecular weight polymeric material and a salt of an organic acid containing at least three carbon atoms. The system may also contain additional ingredients as set out below.

One part of the solvent system of the invention is a low molecular weight polymeric material. As used herein, "a low molecular weight" polymer is any polymer that is liquid or semi-solid at about room temperature and pressure when combined in a solvent system or any polymer that can dissolve in a limited amount of water to form a solvent system. The particular identity of the polymeric entity selected as the solvent will guide one skilled in the art to the appropriate molecular weight for the polymer. Since the polymer will be ingested into the human body, it must be safe and nontoxic (at least when used in the amounts contemplated herein). While the polymer need not be organoleptically pleasing, the polymer preferably does not cause any adverse side reactions or other detrimental effect on humans upon ingestion.

Linear or branched polymers, of course, generally do not have a single molecular weight. Rather, each strand in a polymer sample will have a different length and the "molecular weight" of a polymer sample will be the average molecular weight of the strands.

Acceptable polymers that may be used in the invention include polyalkylene glycols and polyvinyl pyrollidones and analogs thereof, including various copolymers, polymer blends and modified polymers thereof. The polymers of the invention may also include polymeric materials that are not ordinarily thought of as polymers, such as glycerin and propylene glycol. The preferred polymers of the invention are polyols, such as glycerin, propylene glycol and polyalkylene glycols. More preferred are polyethylene glycols and polypropylene glycols. More preferably, the polyethylene glycols of the invention have a molecular weight of less than about 1500, since polyethylene glycol 1500 is reported to be solid at room temperature. (Molecular weights of about 1500 or above are not excluded from the invention to the extent that the polymer may be semi-solid, liquid or soluble in limited amounts of water.) Most preferably, the molecular weight of the polyethylene oxide is from about 400 to about 600 daltons, and the most preferred embodiment of the invention uses polyethylene glycol having a molecular weight of about 600. The solvent may comprise mixtures of materials as well. For example, a polyethylene glycol having a molecular weight of about 600 may be obtained by using PEG 600 or about a 50/50 mixture of PEG 400 and PEG 800.

The polymeric material preferably comprises from about 10% by weight to about 70% by weight of the solution of the invention. More preferably, the polymeric material comprises from about 15% by weight to about 65% by weight of the solution and even more preferably, the polymeric material comprises from about 20% by weight to about 55% by weight of the solution. Most preferably, the polymeric material comprises from about 30% by weight to about 50% by weight of the solution of the invention. When blends of the polymers are used as a solvent, it is preferable, but not critical, that one species of polymer predominates. Thus, in one preferred embodiment of the invention, the solvent system comprises from about 15% to about 65% by weight polyethylene glycol 600 and from 0% to about 5% by weight of (and more preferably from 0% to about 2% by weight) propylene glycol.

In addition to the polymeric material, the invention also comprises a salt of an organic acid containing at least three carbon atoms. The salt helps to ionize the medicament, especially where the medicament is capable of forming a zwitterion, without relying on strong acids or bases.

Preferred cations for the salt are monovalent and divalent cations that are nontoxic and acceptable for human consumption. These cations include, but are not limited to, sodium, potassium, and calcium ions. Alkali cations are preferred, and sodium is the most preferred cation.

The anion of the salt is an organic acid anion containing at least three carbon atoms. Acceptable acid anions include those capable of forming a nontoxic salt with any of the cations of the invention. Although the preferred acid anions are from saturated aliphatic acids having from three to six carbon atoms, other acids are not excluded from the scope of the invention. Aromatic acids, saturated acids having more than six carbon atoms, and unsaturated acids having more than three carbon atoms may be used, so long as the acid forms a nontoxic salt. More preferred acids include mono, di- and tri-carboxylic acids having three to six carbon atoms, including propionic acid, pyruvic acid, citric acid, and butanoic acid. Propionic acid is the most preferred because it has antifungal properties.

In a highly preferred embodiment of the invention, the salt is a sodium propionate salt that is added to the solution of the invention as a salt/water solution. Preferred concentrations of the salt solution are from about 40% by weight to a saturated solution of the salt in water.

The pH of this propionate solution may be adjusted by the addition of small amounts of propionic acid, usually no more than about 1-2% by weight of the propionate solution. So, the numbers in the examples may be slightly incorrect.

The salt may comprise from about 2% by weight to about 40% by weight of the solution of the invention. More preferably, the salt comprises from about 4% to about 35% by weight of the solution of the invention, and even more preferably, from about 4% by weight to about 25% by weight of the solution of the invention. Preferably the pH is adjusted in the salt/water solution to provide acceptable pH limits in the softgel.

The solvent system of the invention may also contain additional ingredients such as cosolvents, including dimethyl isosorbide, oils, including soybean oil, and water. The cosolvent may comprise from 0% by weight to about 30% by weight of the solution of the invention, and more preferably from about 5% by weight to about 20% by weight of the solution of the invention. Most preferably, the cosolvent is dimethyl isosorbide and comprises from about 5% by weight to about 10% by weight of the solution of the invention. Water may comprise from 0% by weight to about 25% by weight of the solution of the invention. Oils may comprise from 0% to about 20% by weight of the solution of the invention, and more preferably from 0% to about 15% by weight of the solution of the invention. In the examples that follow, water is added as part of a sodium propionate solution that is added to the solvent system. In some of these examples, the reported amounts in grams were calculated from the density and volume of the propionate solution added.

The medicament of the invention may be any medicament, but the softgels of the invention are of primary benefit in human consumption, so the medicaments of the invention are preferably those intended for use by humans. Preferred medicaments are those used in over-the-counter treatments of coughs, colds and other common ailments. Thus, highly preferred medicaments include pain relievers, such as aspirin, acetaminophen, naproxen, ibuprofen and other nonsteroidal anti-inflammatory drugs, as well as the so-called "Cox-2" inhibitors. Other highly preferred medicaments include, but are not limited to, cough suppressants, such as dextromethorphan, decongestants, such as pseudoephedrine, and antihistamines, such as chlorpheniramine and doxylamine compounds. Medicaments that form zwitterions when dissolved with the salts of the invention are most highly preferred.

The total amount of medicaments of the invention may comprise from about 25% by weight of the solution up to the amount that will form a fully saturated solution, usually up to about 70% by weight of the solution. Preferably, however, the medicaments comprise from about 30% by weight to about 55% by weight of the solution of the invention. Of course, dosage levels will be adjusted to reflect the needs of the patient, not the needs of the solvent.

Consumer preference suggests that clear or at least translucent solutions should be used in softgels. The solvent system of the present invention may be adjusted to provide such a clear solution acceptable to consumers. In the examples that follow, many of the solutions have a color. The color may be significantly reduced by carrying out the solution process in the absence of oxygen. While the examples used a nitrogen blanket, the solution was exposed to air while various materials were added, which affected the final color of the solution.

The medicament should remain in solution to achieve the benefits of the invention, and the solution should remain stable over time and under conditions normally encountered in consumer applications. The solution disclosed in the present invention has been found stable and robust in a number of tests. For instance, the solution has been placed "on the shelf" at room temperature for extended periods of time, and has remained clear and stable, without precipitation of the medicament. Moreover, the solution has been subjected to alternating refrigeration and room temperature conditions, and the medicament has not crystallized, and has remained stable and clear.

The solution has been placed in softgels successfully, at least on an experimental level. The gelatin in a softgel may be any known on the art. Suitable results have been achieved with Type A gelatin, bloom strength 150. Hydrophilic softgels are preferred.

The selection of ingredients to be used in the solvent system will, of course, depend on the medicament to be administered. Different medicaments, such as naproxen, aspirin and acetaminophen, have different chemical structures and different affinities for various solvent combinations. Highly concentrated solutions of medicaments, such as aspirin and naproxen, require a solvent system tailored to the specific needs of the medicament.

The solution of the invention may be prepared through mixing of the ingredients. This mixing takes place preferably at an elevated temperature and with applied shear. While the applied shear does not necessarily allow for greater solubility of any ingredient, it appears to provide better stability of the solution during handling and storage. Preferably, the solvent is prepared first and the medicament is then added to the solvent. The salt is then also added slowly to help dissolve the medicament. It appears that if the salt is added too quickly, ionization of the medicament does not take place and the material does not form a successful solution. The process may be carried out in whole or in part in a nitrogen atmosphere if the presence of oxygen might discolor or otherwise damage any ingredient in the solution.

Preferred embodiments of the invention have been prepared as described in the examples below. A solution of polyethylene glycol 600 and, optionally, dimethyl isosorbide is prepared in a glass flask, and is stirred at about 250 rpm, and heated to about 50^oC. (An acceptable solution may be prepared without dimethyl isosorbide.) The flask may then be deaerated with nitrogen. Acetaminophen or another medicament is added and a stopper is used to cover the flask. Next, the sodium propionate solution is added dropwise, using a metered flow control device. The formulation is again blanketed with nitrogen and then stirred at about 300 rpm with heat until clear, which usually requires from about 30 to about 120 minutes. Another preferred embodiment incorporates shear to help the materials to blend more quickly and thoroughly.

Claim 1 of 13 Claims

We claim:

1. A pharmaceutically acceptable solution comprising between about 49% and about 70% of a medicament comprising acetaminophen and a solvent system wherein said solvent system comprises a low molecular weight polymeric material and a salt of an organic acid containing at least three carbon atoms.

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