Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1998-11-23
2001-04-24
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S452000, C424S455000, C514S570000
Reexamination Certificate
active
06221391
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to a pharmaceutical solution. More particularly, the present invention relates to a self-emulsifying solution of ibuprofen suitable for encapsulation into a soft gelatin capsule.
BACKGROUND OF THE INVENTION
It is well known in the art that there are solid drugs which are highly insoluble in water. Due to their low solubilities in water, these drugs have a correspondingly low degree of bioavailability. One such drug, in particular, is ibuprofen. Ibuprofen is a non-steroidal anti-inflammatory drug which is commonly used to relieve pain and to treat inflammatory conditions. Ibuprofen is a white powder or crystal which is practically insoluble in water. Ibuprofen is absorbed from the gastro-intestinal tract and the peak plasma concentrations occur approximately one to two hours after ingestion of the solid powder or crystal form.
A standard dosage form widely in use for the delivery of ibuprofen is the solid dosage form or tablet. The absorption time of a solid dosage form (tablet) is relatively long because of two significant factors. The first factor is that the drug; being introduced as a solid, needs to first dissolve before it can be absorbed by the body. The second factor is that absorption into the body is further delayed because ibuprofen is practically insoluble in water or the acidic environment of the stomach.
Several processes have been developed in efforts to increase the solubility and, hence, the bioavailability of ibuprofen. One such prior art process disclosed in U.S. Pat. No. 5,071,643 to Yu et al., discloses the use of a water-based solvent system for enhancing the solubility of an acidic, basic, or amphoteric pharmaceutical agent, such as ibuprofen, to produce a highly concentrated solution suitable for encapsulation. The solvent system includes polyethylene glycol containing 0.2-1.0 mole equivalents of an ionizing agent per mole equivalent of pharmaceutical agent and 1-20% water. This water-based solvent system provides for a highly concentrated solution capable of encapsulation into a small enough vessel, such as a soft gel capsule, to permit easy swallowing and to provide a pharmaceutically effective dose of a pharmaceutical agent such as ibuprofen.
The method disclosed in the Yu et al. reference solubilizes the pharmaceutical agent (ibuprofen) in a water-based solvent system utilizing a solubility enhancing agent to solubilize the ibuprofen.
It would be advantageous and desirable to have an oil-based ibuprofen solution which is capable of supporting ibuprofen concentrations sufficient for encapsulation in a liquid dosage form.
By combining the oil-based ibuprofen solution with a dosage form such as a filled soft gelatin capsule, optimal advantage can be taken of the potential potency and efficacy of the poorly water-soluble ibuprofen. Also, because the formulation is a true solution, content uniformity of dosage is assured. The present invention provides an improved ibuprofen solution and ibuprofen dosage form for providing the relatively water insoluble ibuprofen with a mechanism for greater dissolution and, hence, greater bioavailability than a solid dosage form which includes all of the aforementioned advantages.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a self-emulsifying ibuprofen formulation including a polyoxyethylene castor oil derivative and ibuprofen which increases the stability, concentration, and bioavailability of the scarcely water soluble ibuprofen.
The present invention further provides an ibuprofen dosage form for increasing the stability, concentration, and bioavailability of the scarcely soluble ibuprofen pharmaceutical including a drug delivery vehicle and a liquid formulation including ibuprofen and a polyoxyethylene castor oil derivative disposed within the drug delivery vehicle.
It is a further objective to produce a highly concentrated solution in order to manufacture as small a capsule as possible to facilitate consumer acceptance.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
A self-emulsifying ibuprofen oil-based formulation capable of supporting higher ibuprofen concentrations and having enhanced bioavailability is disclosed. The self-emulsifying ibuprofen formulation generally includes a polyoxyethylene castor oil derivative and ibuprofen.
Polyoxyethylene castor oil derivatives are complex mixtures of various hydrophobic and hydrophilic components. These compounds are non-ionic surfactants which are approved for use in oral, topical, and parenteral pharmaceutical formulations. The polyoxyethylene castor oil derivatives are mainly used as emulsifying and solubilizing agents for the production of aqueous liquid preparations containing oils or hydrophobic substances such as, ibuprofen. Preferred examples of these compounds which are suitable for use in the present invention include Polyoxyl 35 Castor Oil (Peg 35CO) and Polyoxyl 40 Hydrogenated Castor Oil (Peg 40HCO). The amount of the polyoxyethylene castor oil derivatives ranges from approximately 30% to approximately 35% by weight.
For Peg 35CO, the hydrophobic constituents comprise approximately 83% of the total mixture with the main component being glycerolpolyethylene glycol ricinoleate. The hydrophilic component (approximately 17%) consists of polyethylene glycols and glycerol ethoxylates. Peg 35CO has an HLB value of approximately 12-14.
For Peg 40HCO, the hydrophobic component is approximately 75% of the total mixture. The hydrophobic component is comprised mainly of fatty acid esters of glycol polyethylene glycol and fatty esters of polyethylene glycol. The hydrophilic fraction (approximately 25%) consists of polyethylene glycols and glycerol ethoxylates. Peg 40HCO has an approximate BLB value of 14-16.
Ibuprofen is solubilized in the polyoxyethylene castor oil derivatives, preferably Peg 35CO and/or Peg 40HCO to produce a solution which is suitable for encapsulation into a drug delivery vehicle such as a soft gelatin capsule. The resultant solution of ibuprofen in the surfactants produces a solution that is water miscible and self-emulsifying upon addition to water. The amount of the ibuprofen in the formulation ranges from approximately 33% to 38% by weight.
It is possible to dissolve large amounts of ibuprofen in only the polyoxyethylene castor oil derivative surfactants described above at an elevated temperature; however, recrystallization can occur upon cooling of the solution to ambient temperatures. In order to prevent the recrystallization of ibuprofen from the solution upon cooling, solution concentrations at ambient temperatures can be enhanced and stabilized by the addition of complexing agents which are designed to prevent the recrystallization of the drug (ibuprofen). One such class of compounds is soluble polyvinyl pyrrolidone (PVP). PVP is a polymeric compound formulated to specific molecular weights which can range from approximately 2000 to 1,500,000 Daltons. PVP has the capacity or property of forming water-soluble complexes with water insoluble drug substances such as ibuprofen. Typically, higher molecular weight PVP's are used as thickeners while low molecular weight PVP's are typically used as solubilizers or crystallization inhibitors. In the present invention, two particular PVP's are of interest: PVP K-12 (molecular weight approximately 2000-3000 Daltons) and PVP K-17 (molecular weight approximately 7000-11,000 Daltons) which are both suitable recrystallization inhibitors. The amount of PVP utilized in the present invention can range from approximately 15-20% in order to prevent recrystallization. Additionally, in order to aid in dissolution of the PVP in the formulation, water may be utilized as required wherein the minimum required amount is approximately 1-2%. It should be noted, that peculiar to the present invention, that the water content is only approximately 20% of the water content which would be required to dissolve the PVP alone. The balance of the PVP is being dissolved by the system although PVP is not soluble i
Accucaps Industries Limited
Gifford, Krass, Groh Sprinkle, Anderson & Citkowski, P.C.
Kishore Gollamudi S.
Ware Todd D.
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