The invention herein provides for an oral pharmaceutical composition adapted for use in capsular dosage forms comprising acetaminophen and a lactate salt alone or in combination with an acetate salt. Compositions of the invention exhibit improved solubility characteristics of the active ingredient per given fill volume, thereby permitting the use of smaller capsule sizes to deliver a given effective dose of the active ingredient. Compositions of the invention also exhibit improved clarity per concentration of active ingredient. The invention also provides for a capsular dosage form containing the composition.

SUMMARY OF THE INVENTION

The invention herein provides for an oral pharmaceutical composition for use in capsular dosage forms comprising acetaminophen and lactate salts alone or in combination with acetate salts which exhibit improved solubility characteristics of the active ingredient while at the same time permitting the use of smaller capsule sizes to deliver effective doses thereof. In a preferred composition, the combination of l-lactate (levos) and acetate salts are used in the composition. Furthermore, compositions have improved visual characteristics, e.g., clarity of appearance. The invention also provides for a capsular dosage form, such as a soft or hard gelatin capsule, containing such a composition.

Acetaminophen is difficult to dose in a solubilized form due to high therapeutic dose requirements (typically 500 to 1,000 mg) while still using a relatively small appropriate capsule size for patient compliance. It has been discovered that combinations of particular ingredients when used in conjunction with acetaminophen in a liquid fill composition, not only improve the solubility of the acetaminophen thereby permitting increased concentrations of the active ingredient for a given fill, but also improves the appearance of the fill composition as well by way of reduced observable crystallization. In particular, certain combinations of acetaminophen and solvent system comprising lactate salts alone, or both lactate salts and acetate salts, provide such improvements while at the same time provide formulations compatible with capsular encasing materials, such as gelatin.

In one aspect, the invention provides for a liquid oral pharmaceutical composition adapted for use in capsular dosage forms comprising acetaminophen as an active ingredient and a solvent system comprising an alkali metal lactate salt. Preferred alkali metal lactate salts are alkali metal l-lactate salts. Even more preferred as the alkali metal lactate salt is sodium l-lactate. The lactate salt can be used alone as the carboxylate salt, or preferably, together with an alkali metal acetate salt. When the combination is used, the preferred acetate salt is potassium acetate. The solvent system of the composition of the invention can further comprise polyethylene glycol and polyvinyl pyrrolidone.

Another aspect of the invention provides for a capsular dosage form containing a liquid pharmaceutical composition comprising acetaminophen as an active ingredient and a lactate salt, preferably a l-lactate salt. Suitable capsular dosage forms include, but are not limited to, capsule casings composed of gelatin, such as soft or hard gelatin.

One advantage of the invention is that concentrations of acetaminophen greater than about 40% by weight, and even about 42%, can be achieved per given volume, while still maintaining clarity of appearance of the composition. Furthermore, the composition is suitable for use in capsular materials subject to degradation, such as gelatin. For a given dosage size such as 325 mg, acetaminophen can be present in an amount of about 42% by weight of the fill composition. Accordingly, smaller capsule sizes and/or fewer capsules need to be used to deliver the same effective dose.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the general term "capsule" is intended to encompass any suitable one-piece capsular containment adapted for oral ingestion and which is adapted for use in conjunction with liquid fill compositions. The term includes capsules having casings composed of soft and hard materials, such as gelatin, starches, celluloses, hydrocolloids, gums, carageegans, or any other natural or synthetic material which can be used to encapsulate the liquid composition and be ingested by an animal. The term is intended to include a variety of capsule shapes and sizes, and is not intended to limit the dosage form to a specific type or shape.

The term "acetaminophen" as used herein is intended to include the chemical derivatives of the acetaminophen structure having equivalent pharmaceutical effect.

The invention generally includes a liquid oral pharmaceutical composition adapted for use in capsular dosage forms. Specifically, the capsular dosage forms suitable for use with the invention are those which are adapted to contain liquid fill compositions. A variety of capsule casing materials can be used in conjunction with the invention, providing they permit one-piece integrated molding manufacturing techniques. Examples of suitable casing materials include, but are not limited to, gelatin (soft and hard), starches, celluloses, carageegans, hydrocolloids, gums, and the like. Casing materials can be prepared using well-known and conventional techniques and materials readily available in the art.

The shape and size of capsules can vary in accordance with the invention. In addition to the conventional oblong shape, the capsules can be in the form of a sphere, oval, tablet, and the like. The size of the capsule used will vary in accordance to the volume of the fill composition intended to be contained therein.

The active ingredient of the composition of the invention is acetaminophen and chemical derivatives thereof having equivalent pharmaceutical effect. The amount of acetaminophen used in the pharmaceutical composition will depend upon the amount of the drug desired to be administered in the dosage form while maintaining the solubility and clarity characteristics of the entire composition including the solvent system.

The invention includes a solvent system for acetaminophen which comprises an alkali metal lactate salt. In particular, preferred for use in the solvent system of the invention are alkali metal l-lactate salts, such as sodium l-lactate. In preparing compositions of the invention, the solvent system to be used can contain the l-lactate salt alone or, preferably, in combination with an alkali metal acetate salt. When the acetate salt is used, potassium acetate is preferred. Surprisingly, it has been discovered that not only are the desirable properties of the fill composition obtained by virtue of the particular number of carbon atoms in the carboxylate chain used in the solvent system, but also are affected by the specific rotational chemistry of the carboxylate salt. In other words, not only are the best results obtained using lactate as compared to other carboxylate salts, but in particular l-lactate (levo) as compared to racemic dl-lactate salts. The highest concentrations of acetaminophen per given total fill volume can be obtained using l-lactate salt as the carboxylate salt. Alternatively and preferably, the concentration of acetaminophen per given fill volume can be increased even more when the combination of l-lactate and an acetate salt, such as potassium acetate, are used simultaneously.

The composition of the invention further includes within the solvent system polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP). In a preferred embodiment, the polyethylene glycol is polyethylene glycol 600 (available from Union Carbide, Danbury, Conn.). Suitable polyvinylpyrrolidone includes Povidone 25 (available from BASF, Mount Olive, N.J. and ISP, Freetown, Mass.).

The amounts of each ingredient of the solvent system can vary slightly provided the solubility characteristics of acetaminophen and the desirable clarity of the overall fill composition are maintained. The lactate salt can generally be present in an amount ranging from about 4.0% to about 12.3% by weight of the fill composition. When present, the acetate salt can be present in an amount ranging from about 4.0% to about 7.0% by weight of the fill composition. When both l-lactate and acetate salts are used, the amount of l-lactate can be lower relative to the use of l-lactate alone in the solvent system. Polyethylene glycol can be present in an amount ranging from about 30.0% to about 40.0% by weight of the fill composition. Polyvinyl pyrrolidone can be present in an amount ranging from about 3.0% to about 7.0% by weight of the fill composition.

In the interest of minimizing the overall fill volume while maximizing the concentration of the active ingredient, the use of additional ingredients is possible but not recommended. The invention offers the advantage of making available the administration of a given dosage amount of active ingredient using smaller capsule sizes, thereby increasing patient comfort and compliance, as well as reduced packaging and materials volume. The clarity of the pharmaceutical fill composition provides a more appealing appearance and affords the ability to utilize visually appealing transparent capsule casing materials, as compared to compositions producing a cloudy or milky appearance.

Pharmaceutical compositions of the invention can be prepared generally using the basic preparation steps of initially solubilizing polyvinyl pyrrolidone in polyethylene glycol by mixing them together at a temperature of about 30° C. for approximately 15 to 20 minutes until the polyvinyl pyrrolidone is completely solubilized. The active ingredient, acetaminophen, can then be added to the mixture at high speed for a period ranging from about 30 minutes to about 45 minutes. During the addition step of acetaminophen, the temperature of the mixture can be slowly increased to about 65° C. and maintained. The carboxylate salts, i.e., lactate or lactate and acetate, and water can then be added. The temperature of the mixture can be increased to about 70° C. The mixture can be continuously stirred for a period ranging from about 1 hour to about 2 hours, while maintaining the temperature.

Conventional capsule manufacturing techniques and equipment can be used to prepare the composition-filled capsules of the invention. Typically, ribbon and die roller manufacturing techniques are suitable for preparation of the capsules of the invention. Encapsulation apparatuses such as that described in Stroud et al. U.S. Pat. No. 5,735,105, the entire text of which is incorporated by reference herein, can be used.
 

Claim 1 of 15 Claims

1. An oral liquid pharmaceutical composition in a capsule comprising:

acetaminophen as an active ingredient and a solvent system comprising a l-lactate salt.
 

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