WO2009009737A1

WO2009009737A1 - Sustained release formulation of active pharmaceuticals in a lipid based sustained release

Info

Publication number: WO2009009737A1
Application number: PCT/US2008/069798
Authority: WO
Inventors: Krishna Vishnupad
Original assignee: Neurosci, Inc.
Priority date: 2007-07-12
Filing date: 2008-07-11
Publication date: 2009-01-15

Abstract

A pharmaceutical formulation is disclosed providing sustained release dosage forms of valproic acid (VPA), its esters, salts or its primary amide, thereof, in combination with a predetermined quantity of one or more additives which are physiologically acceptable and which results in the desired gradual and sustained release of the drug. Valproic acid is mixed with hydrophobic material like waxes, oil, lipids, fats, phospholipids, glycerides, vegetable oils, peanut oil, com oil, soybean oil. esters, and other lipophillic material such as isopropyl monsterate, ethyl sterate, cetyl alcohol, stearyl alcohol and other fatty acids. There may also be used in combinations thereof, or a combination with other fatty acids known in the art.

Description

SUSTAINED RELEASE FORMULATION OF ACTIVE PHARMACEUTICALS IN A

LIPID BASED SUSTAINED RELEASE

RELATED APPLICATION

This application claims the benefit of the filing date of U.S. Provisional Application No. 60/949,303, filed July 12, 2007, hereby incorporated in its entirety by reference.

FIELD OF DISCLOSURE

The present disclosure relates to pharmaceutical formulations. More particularly, the present disclosure concerns a formulation comprising valproic acid, a pharmaceutically acceptable salt, ester, or amide thereof, or divalproex sodium, in a lipid based sustained release formulation. These lipid based sustained release dosage forms have an improved pharmacokinetic profile and advantageously are able to deliver large dosage forms in acceptable pharmacokinetic rates. These dosage forms minimize the variance between peak and trough plasma levels of valproate, resulting in a more desirable dosing plasma level that allows a reduction in the incidence of side effects.

BACKGROUND OF DISCLOSURE

2.Propylpentanoic acid, more commonly known as valproic acid ("VPA") is effective as an antiepilpetic agent. After ingestion, the free acid dissociates to the valproate ion within the gastrointestinal tract. The valproate ion is absorbed and produces an antiepilpetic therapeutic effect. Physicians Desk Reference ("PDR"), 52^nd Edition, page 426 (2007). The acid moiety of valproic acid has been functionalized in order to produce prodrugs capable of generating a valproate ion in-vivo. For example, the amide of valproic acid, valpromide ("VPO"), has been produced, as well certain salts and esters of the acid.

Despite the efficacy of these drugs in the treatment of conditions such as epilepsy, they all suffer from a common disadvantage, as these valproate compounds have a relatively short half life. For example, the half life of valproic acid is reported to be between six and seventeen hours in adults and between four and fourteen hours in children. This leads to substantial fluctuations in the plasma concentration of the drug, especially in chronic administration and causes dosing problems resulting in an increase incident of side effects.

In current instant release preparation, in order to maintain reasonably stable plasma concentrations, it is necessary to resort to frequent dosing. The resulting inconvenience to the patient often results in lowered compliance with the prescribed dosing regimen. Unfortunately, the widely fluctuating plasma concentrations of the drug may result in administration of drug outside of the therapeutic window resulting in less than effective therapeutic amounts of the drug in a conservative dosing regimen, or amounts too large for the particular patient in an aggressive dosing regimen. Various attempts to solve these dosing problems have been in the form of standard controlled release formulations utilizing common formulation technology to develop controlled release dosage forms that decrease the dosing frequency of the compounds.

Unfortunately, the pharmacokinetics of valproic acid, and other valproate compounds, has complicated such development efforts as the nonlinear, concentration dependent protein binding of valproate, has proven to be problematic in standard formulation approaches. As the dose of valproate increases, serum levels rise faster than might be expected since proportionately less of the dose is bound to plasma proteins. These nonlinear kinetics significantly increase the difficulty of designing sustained release dosage forms. Identical doses of the valproate compound can produce vastly different blood levels depending upon the rate at which the valproate compound is released from the dosage form.

Further complicating formulation efforts is the fact that a correlation between valproate levels and efficacy is unknown for disease states other than epilepsy. What impact valproate levels play in a number of side effects is also unknown at the present time. GI irritation is very common in patients consuming valproate, affecting almost one third of patients. The problem with GI irritation and other common side effects increases at elevated doses. Other side effects such as asthenia, dizziness, somnolence, alopecia, and weight gain are prevalent and like GI irritation increase at elevated doses.

Prior attempts to solve dosing problems associated with the nonlinear kinetics have been to find other forms of the active ingredient which is more desirably released to the body or formulations that deliver the active ingredient by either a timed- or controlled-release 5 mechanisms. The following patents describe some of the attempts to produce formulations or utilize alternative forms of the active ingredient to achieve desirable plasma levels.

U.S. Pat. No. 5,055,306 to Barry, et al. discloses an effervescent or water-dispersible granular sustained release formulation suitable for use with a variety of therapeutic agents. The granules comprise a core comprising the active ingredient and at least one excipient, and a water ) insoluble, water-swellable coating comprising a copolymer of ethyl acrylate and methyl methacrylate and a water soluble hydroxylated cellulose derivative. U.S. Pat. No. 5,169,642 to Brinkler, et al. discloses a sustained release dosage form comprising granules of divalproex sodium or amides or esters of valproic acid coated with a sustained release composition comprising ethyl cellulose or a methacrylic methyl ester, a plasticizer, a de-tackifying agent, and a slow-release polymeric viscosity agent.

Despite the apparent numerous therapeutic advantages of valproate therapy, certain patients consuming these medications unfortunately experience side effects. For example, with divalproex sodium delayed release tablets, approximately 7% of patients report alopecia (hair loss). Up to approximately 8% of patients report significant weight gain.

Likewise, up to one-third of patients consuming divalproex sodium delayed release tablets complain of nausea. Unfortunately, the nausea can lead to non-compliance and subsequent worsening of the patient's condition. Dizziness, tremor, asthenia, somnolence are also common with valproate therapy. The impact of plasma levels on these side effects is also unknown.

Despite all of prior formulation attempts, there remains a need for a sustained release formulation of divaproex sodium, and other valproate compounds, that will permit once-a-day dosing that achieve a desired pharmacokentic profile. Unfortunately, there remains the need for a pharmaceutical formulation which will effectively maintain plasma concentrations of the active ingredient at more constant levels over a 24 hour dosing period. Further, sustained release formulations are needed that will maintain plasma levels within the therapeutic window thereby decreasing the incidence of side effects associated with valproate therapy, such as nausea, vomiting, asthenia, somnolence, alopecia, weight gain. SUMMARY OF DISCLOSURE

In accordance with the present disclosure, a new oral sustained release formulation is disclosed. Orally administered sustained release dosage forms of valproic acid (VPA), its sodium salt: sodium valproate (SVP), its primary amide: valpromide (VPD), and other derivatives of therapeutic value such as 2-propylpentanol-di-n-propylacetate, glycerol tri- dipropylacetate and di sodium valproate are provided. The sustained release dosage forms of the active ingredient are based on a desired gradual release of the active ingredients in the biological fluids, resulting in a sustained action of the valproic acid with but small fluctuations of the plasma level over prolonged periods of time. In accordance with the present disclosure, the sustained release of valproic acid results in desirable pharmacokinetics thereby improving patient compliance and reducing the incidence of side effects.

According to one illustrative embodiment of the disclosure there are provided dosage forms of valproic acid (VPA), its esters, salts or its primary amide, thereof, in combination with a predetermined quantity of one or more additives which are physiologically acceptable and which results in the desired gradual and sustained release of the drug. In a first illustrative embodiment valproic acid is mixed with hydrophobic material like waxes, oil, lipids, fats, phospholipids, glycerides, vegetable oils, peanut oil, corn oil, soybean oil, esters, and other lipophillic material such as isopropyl monsterate, ethyl sterate, cetyl alcohol, stearyl alcohol and other fatty acids. There may also be used in combinations thereof, or a combination with other fatty acids known in the art.

In another illustrative embodiment the hydrophobic drug mixture also contains surfactants like Poloxamer 407, TPGS or other oil in water emulsifiers having HLPB values of about 6 to about 14. Without being bound to a particular theory, it is thought that this combination allows an active ingredient with the hydrophobic material to be solublized in an aqueous media, providing a sustained release of the active ingredient.

In yet a further illustrative embodiment the active ingredient within a hydrophobic material can be encapsulated in either a hard gelatin capsule or a soft gelatin capsule. It is contemplated within the scope of the disclosure that the active ingredient within a hydrophobic material can be combined with other active pharmaceuticals within a capsule in a capsule dosage form.

In another illustrative embodiment an active ingredient with the hydrophobic material is solubalized in an aqueous media leading to a formation of a micro-emulsion, which it is thought provides a more predictable absorption than prior forms of valproic acid or di-sodium valproate.

In yet a further illustrative embodiment the pharmaceutical formulation according to the disclosure contains a pharmaceutical active ingredient from about 10 to about 80 by weight of the total formulation.

In a further illustrative embodiment according to the disclosure valproic acid, which is liquid in nature, is formed into a semisolid gel using the hydrophobic material according to the disclosure. It is thought that the semisolid gel containing valproic acid is stable in a hard or soft gelatin capsule.

In another illustrative embodiment a pharmaceutical active ingredient with the hydrophobic material is solubalized in an aqueous media leading to a formation of a micro- emulsion, which it is thought provides a more predictable absorption of higher doses. In one illustrative embodiment an active ingredient such as gabapentene in a place within the lipid sustained release form according to the disclosure including but not limited to doses of 900mg and 1200mg.

In yet a further illustrative embodiment the active ingredient within a hydrophobic material can be encapsulated in either a hard gelatin capsule or a soft gelatin capsule. It is contemplated within the scope of the disclosure that the active ingredient within a hydrophobic material can be combined with other active pharmaceuticals within a capsule in a capsule dosage form. This active pharmaceutical within a capsule in a capsule dosage form can be utilized, among other dosage forms, to place a liquid active pharmaceutical or nutritional supplement with non compatible liquid or solid active pharmaceutical or nutritional supplement. In one illustrative embodiment for liquid drug with a solid drug, in a sustained release form, omega 3 is combined with aspirin. In a further illustrative embodiment omega 3 is combined with other cardiovascular products, like niacin in sustained release form.

BRIEF DESCRIPTION OF THE DRAWINGS

Advantages of the present invention will become apparent to those skilled in the art upon reading and understanding the following detailed description with reference to the accompanying figures.

FIG. IA represents Mean Plasma Concentrations Vs Time Curve for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulation. (N=I 1);

FIG. IB represents Log Mean Plasma Concentrations Vs Time Curve for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulation (N=I 1); FIG. 2A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;

FIG. 2B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.

FIG. 3A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;

FIG. 3 B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.

FIG. 4A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;

FIG. 4B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.

FIG. 5A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject; FIG. 5B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.

FIG. 6A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;

FIG. 6B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.

FIG. 7A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;

FIG. 7B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.

FIG. 8A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;

FIG. 8B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;. FIG. 9A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;

FIG. 9B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.

FIG. 1OA represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;

FIG. 1OB represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.

FIG. 1 IA represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;

FIG. 1 1 B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.

FIG. 12A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject; FIG. 12B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.

DETAILED DESCRIPTION OF THE DISCLOSURE

Detailed embodiments of the present disclosure are disclosed herein, however, it is to be understood that the disclosed embodiments are merely exemplary of the disclosure, which may be embodied in various forms. Therefore, specific functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed embodiment.

The amount of the hydrophobic material in the dosage form generally varies from about 10% to about 80% by weight of the composition. Preferably, the amount of hydrophobic material varies from about 25% to about 45% by weight of the dosage form. Most preferably, the amount of hydrophobic material varies from about 30% to about 40% by weight of the dosage form.

The formulation according to the disclosure also typically includes pharmaceutically acceptable excipients such as diluents or fillers. Diluents, or fillers, are added in order to increase the mass of an individual dose to a size suitable for the hard or soft gelatin capsule. Suitable diluents or fillers include olive oil, vegetable oil such as castor oil, etc.

According to one illustrative embodiment of the disclosure there are provided dosage forms of valproic acid (VPA), its esters, salts or its primary amide, thereof, in combination with a predetermined quantity of one or more additives which are physiologically acceptable and which results in the desired gradual and sustained release of the drug. In a first illustrative embodiment valproic acid is mixed with hydrophobic material like waxes, oil, lipids, fats, phospholipids, glycerides, vegetable oils, peanut oil, com oil, soybean oil, esters, and other lipophillic material such as isopropyl monsterate, ethyl sterate, cetyl alcohol, stearyl alcohol and other fatty acids. There may also be used in combinations thereof, or a combination with other fatty acids known in the art. In a first illustrative embodiment oil used as a filler in the formulation. It is contemplated within the scope of the disclosure that other vegetable oils, plant oils and the like may be used as fillers in the formulation. In one particular embodiment Hydrogenated castor oil is used in combination with a surfactant as a rate controlling agent. As it is known in the art, water penetrates castor oil slowly allowing active ingredients contained therein to be released in a gradual manner.

In another embodiment according to the disclosure, Poloxamer 407, a hydrophilic non- ionic surfactant of the more general class of copolymers known as poloxamers is used within the formulation for forming a micro-emulsion. It is a surfactant widely used for dissolving oily ingredients in water. Poloxamer 407 is a triblock copolymer consisting of two hydrophilic blocks (poly-ethylene glycol) separated by a hydrophobic block (poly-propylene glycol). The approximate lengths of the two PEG blocks is 101 repeat units while the approximate length of the propylene gycol block is 56 repeat units. This particular compound is also known by the BASF trade name Lutrol F- 127®.

In a further illustrative embodimetn according to the disclosure, Glyceryl Monooleate is added to the formulation. Glyceryl monooleate is prepared by esterification of commercial oleic acid that is derived either from edible sources or from tall oil fatty acids. It contains glyceryl monooleate (C21H40O4, CAS Reg. No.25496-72^4) and glyceryl esters of fatty acids present in commercial oleic acid. It is a lipophilic emulsifier for water-in-oil applications. It is widely used as an excipient in antibiotics and other drugs. It is insoluble in water and it can form a micro-emulsion in water. The hydrophilic-lipophilic balance (HLB) is about 3.8.

According to the disclosure, an emulsifying agents can be used to solubilize oily substances in water. The choice of a suitable emulsifier or a combination of emulsifiers can readily be made by those in the field. Surfactants which may be used for this purpose have preferably HLB value of 1 to about 20. Examples of them are reaction products of natural or hydrogenated vegetable oils, and ethylene glycol; i.e., polyoxyethylene glycolated natural or hydrogenated vegetable oils: for example polyoxyethylene glycolated natural or hydrogenated castor oils. Surfactants commercialized under the trade names Cremophor RH-40, Cremophor RH60, Cremophor EL, Nikkol HCO-40 and Nikkol HCo-60 may be used in the composition according to the present disclosure. Cremophor RH40 and Cremophor El are preferred.

It is also contemplated within the scope of the disclosure that polyoxyethylene sorbitan fatty acid esters: e.g., mono- and tri-lauryl, palmityl, stearyl and oleyl esters; e.g. products of the trade name "Tween," which includes polyoxyethylene sorbitan mono-laurate (Tween), polyoxyethylene sorbitan mono-palmitate (Tween 40), polyoxyethylene sorbitan mono-oleate (Tween 80), etc. depending on the kind of fatty acid. Tween 20 and Tween 40 can be used preferably in the composition according to the present disclosure.

It is further contemplated within the scope of the disclosure that polyoxyethylene fatty acid esters: for example, polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj as well as polyoxyethylene fatty acid esters known and commercially available under the trade name "Cetiol HE" can be used in the composition according to the present disclosure.

It is also contemplated within the scope of the disclosure that D-alpha-tocopheryl succinate (TPGS) can be used as an absorption and bioavailability enhancer in the composition according to the disclosure. TPGS is synthesized by esterifying d-alpha tocopheryl succinate with polyethylene glycol (PEG) 1000 (the molecular weight of PEG 1000 is approximately 1,000 daltons). It is a pale yellow, waxy solid substance that is amphipathic and hydrophilic. Its molecular weight is approximately 1 ,513 daltons. d-alpha-tocopherol comprises 26% of TPGS. TPGS is also known as d-alpha-tocopheryl polyethylene glycol 1000 succinate and d-alpha- tocopheryl PEG 1000 succinate. Alpha-tocopheryl polyethylene glycol succinate, abbreviated as TPGS, is a water-soluble derivative of d-alpha-tocopheryl succinate. TPGS is also known as d- alpha-tocopheryl polyethylene glycol 1000 succinate and d-alpha-tocopheryl PEG 1000 succinate. Since there are eight stereoisomers of alpha-tocopherol, the designation d-alpha- tocopherol, although commonly used, is chemically incorrect. Correct chemical names for TPGS include RRR-alpha-tocopheryl polyethylene glycol 1000 succinate, 2R, 4'R, 8'R-alpha- tocopheryl polyethylene glycol 1000 succinate and 2, 5, 7, 8-tertramethyl-2-(4',8',12'- trimethyltridecyl)-6-chromanyl polyethylene glycol 1000 succinate.

In a first illustrative embodiment the hydrophobic drug mixture also contains surfactants like Poloxamer 407, TPGS or other oil in water emulsifiers having HLPB values of about 6 to about 14. Without being bound to a particular theory, it is thought that this first combination allows an active ingredient with the hydrophobic material to be solublized in an aqueous media, providing a sustained release of the active ingredient. In yet a further illustrative embodiment the active ingredient within a hydrophobic material can be encapsulated in either a hard gelatin capsule or a soft gelatin capsule. It is contemplated within the scope of the disclosure that the active ingredient within a hydrophobic material can be combined with other active pharmaceuticals within a capsule within a capsule dosage form.

Other excipients that may be incorporated into the formulation include preservatives, antioxidants, or other excipients commonly used in the pharmaceutical industry, etc. The amount of excipients used in the formulation will correspond to that typically used in a gelatin capsule. The total amount of excipients, fillers and extenders, etc. varies from about 10% to about 80% by weight of the dosage form.

The compositions of the disclosure can be administered orally in the form of hard gelatin capsules or soft gelatin capsules. The gelatin capsules can be prepared by techniques known in the art and contain a therapeutically effective amount of the valproate compound and such excipients as are necessary to form the capsule by such techniques. The gelatin capsule can additionally be prepared with enteric coatings and other release-controlling coatings for the purpose of acid protection, easing swallow ability, etc. The coating may be colored with a pharmaceutically accepted dye or pigment. The amount of dye and other excipients in the coating liquid may vary and will not impact the performance of the sustained release gelatin capsules.

In one illustrative embodiment the coating liquid generally comprises film forming polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose esters or ethers such as cellulose acetate or ethylcellulose, an acrylic polymer or a mixture of polymers. The coating solution is generally an aqueous solution or an organic solvent further comprising propylene glycol, sorbitan monoleate, sorbic acid, fillers such as titanium dioxide, a pharmaceutically acceptable dye.

In a further illustrative embodiment according to the disclosure a gelatin capsule comprises from about 50 weight percent to about 55 weight percent of an active ingredient selected from the group consisting of valproic acid, a pharmaceutically acceptable salt or ester of valproic acid, divalproex sodium, and valpromide; from about 20 weight percent to about 40 weight percent of hydrophobic material; from about 5 weight percent to about 15 weight percent of fillers or diluents, from about 1 weight percent to about 6 weight percent of surfactants; and all weight percentages based upon the total weight of the gelatin capsule.

As noted above, the gelatin capsule according to the disclosure that meets the dissolution profile depicted in table 1 will provide two therapeutic goals. First, it will provide a dosage form of valproate that will maintain desired effective therapeutic levels of the valproate ion over a 24 hour dosing period, thus providing once daily dosing. Secondly, it will reduce the incidence of side effects associated with valproate therapy. Formulations matching the dissolutions profiles set forth in table 1 , will provide the pharmacokinetic profile described below.

In order to obtain these benefits, it is necessary for the once-a-day valproate dosage form to achieve certain pharmacokinetic parameters, when compared to a BID valproate dosage form. The daily dosage form must reduce peak plasma levels of valproate ("C_max ") without significantly impacting either trough levels ("C_1111n ") or the extent of valproate absorption

("AUC"). C_max for the daily dosage form should be statistically significantly lower than the C_maχ for a bid dosage form of the same valproate compound, when each is measured at steady state in a fasting population. For example, a once-a-day sustained release divalproex sodium dosage form will exhibit a C_max that is statistically significantly lower than that produced by a divalproex sodium delayed release tablet, when each is measured at steady state in a fasting population. Typically, peak plasma levels of valproate are reduced at least 10%. More typically, these peak plasma levels are reduced up to about 20%. This reduction must be accomplished with out any significant reduction in trough levels or total absorption of valproate.

C_m!,, for the daily dosage form should not be statistically significantly different from that obtained with a bid dosage form of the same valproate compound, when each is determined at steady state in a fasting population. More specifically, C_1111n for a once-day sustained release divalproex sodium dosage form should not be statistically significantly different from that obtained with a delayed release divalproex sodium tablet when each is measured at steady state in a fasting population.

In addition to reducing peak valproate levels as described above, it is also important that the total amount of valproate absorbed from the daily dosage form not be decreased significantly, when compared to a bid dosage form of the same valproate compound over a 24 hour dosing interval. Total drug absorption is also referred to as AUC (area under the curve).

It is thought that the incidence of side effects can be reduced significantly by reducing peak plasma levels of valproate by approximately 10-20%. The literature suggests that the correlation between side effects and plasma valproate levels is unknown. Formulations meeting the dissolution profiles above will exhibit this reduced incidence of side effects. The following non-limiting examples are presented in order to illustrate the disclosure. These examples should not be construed in any manner to limit the present disclosure.

EXAMPLES

Example I Valproic Acid sustained release soft gelatin capsule or hard gelatin capsule

Valproic Acid 500 mg

Olive oil 15-40 mg

Hydrogenated Castor oil 50-90 mg

Poloxamer 407 50-90 mg Glyceryl Monololeate 15-35 mg

Cremophor RH40 5-25 mg

TPGS 0-15 mg

Soft gelatin capsule shell is gelatin based (TSE/BSE free)

Example II Valproic Acid sustained release soft gelatin capsule or hard gelatin capsule

Valproic Acid 500 mg

Cernauba Wax 30-60 mg

Micro wax 2-10 mg

Glyceryl belerate 30-60 mg White wax 10-25 mg

Paloxamer 407 50- 100 mg

TPGS 0-15 mg

Soft gelatin capsule shell is gelatin based (TSE/BSE free) Example III

The desired release rate for the gelatin based capsule in examples 1 and 2 in a standard dissolution test in 45 minutes in acid and 1-24 hours in buffer are as follows: Table 1

If the gelatin based capsule in examples 1 and 2 are enteric coated then the dissolution test in 45 minutes in acid is about 0-10%. In alkaline conditions the dissolution test in 45 minutes is about 0-20%

Example IV

The following example provides a summary of the experimental work regarding the dissolution profiles of several formulations according to the disclosure. The following formulations were encapsulated into soft gelatin capsules as shown in table 2 and their respective dissolution profile data is contained within table 3. Table 2

Table 3

Example V

Patients were dosed with Valproic acid sustained release soft gel capsules 500mg according the disclosure (test formulation). Table 4 is a summary of pharmacokinetic values for the test formulation under fasting conditions. Table 5 is a summary of concentration at time intervals for the test formulation under fasting conditions. Table 4

Table 5

Table 5 (Continuation A) Dru Concentration Data in μg/mL of Valproic Acid for Test (T) Formulation

Table 5 (Continuation B)

Drug Concentration Data in μg/mL of Valproic Acid for Test (T) Formulation

Note: LOQ = 2.039 μg/mL, the values below LOQ are reported as 0.000. While there have been shown and described what are the preferred embodiments of the disclosure, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the formulations and process can be made without departing from the scope of the disclosure as it is defined by the appended claims.

Although the illustrative embodiments disclose the use of valproate compounds in a lipid based formulation, it will be apparent to those skilled in the art that other active pharmaceutical agents can be used in combination with the valproate compounds. Likewise, it will be understood that other active pharmaceutical compounds would benefit from these disclose lipid based delivery system including but not limited to active pharmaceuticals such as gabapentene.

Although the illustrative embodiments disclose the use of valproate compounds in a lipid based formulation in a soft for hard gelatin capsule, it will be apparent to those skilled in the art that other active pharmaceutical agents can be used in combination with the valproate compounds within the same gelatin capsule in within a further capsule within the capsule. Likewise, it will be understood that other active pharmaceutical compounds that would benefit from a combination therapy with the valproate compounds, but are incompatible in the same dosage form could benefit from a capsule in a capsule formulation.

Although the illustrative embodiments disclose the use of valproate compounds in a lipid based formulation in a soft for hard gelatin capsule, it will be apparent to those skilled in the art that other active pharmaceutical agents can be used in the lipid based formulation according to the invention. Likewise, it will be understood that other active pharmaceutical compounds that would benefit from a combination therapy, but are incompatible in the same dosage form could benefit from a capsule in a capsule formulation. It will be appreciated by those skilled in the art that incompatible liquids or incompatible solids and liquid pharmaceuticals will benefit from the lipid based formulation according to the disclosure and the use of capsule within capsule dosage form.

The invention may be embodied in other forms without departing from the spirit or essential characteristics thereof. The embodiments disclosed in this application are to be considered in all respects as illustrative and not limiting. The scope of the invention is indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

What is claimed is:

1. A hydrophobic pharmaceutical delivery system comprising: an active pharmaceutical agent from about 40 to about 80 w/w %; said active pharmaceutical agent is in an admixture with about 20 to about 50 % of a pharmaceutically acceptable lipid; and an emulsifying agent.

2. The hydrophobic pharmaceutical delivery system according to claim 1 wherein said pharmaceutical agent is selected from the group consisting of valproic acid , sodium valproate , valpromide, 2-propylpentanol-di-n-propylacetate, glycerol tri- dipropylacetate and di sodium valproate.

3. The hydrophobic pharmaceutical delivery system according to claim 1 wherein said pharmaceutically acceptable lipid is selected from the group consisting of oil, lipids, fats, phospholipids, glycerides, vegetable oils, peanut oil, corn oil, soybean oil, esters, isopropyl monsterate, ethyl sterate, cetyl alcohol, stearyl alcohol, fatty acids and combinations thereof.

4. The hydrophobic pharmaceutical delivery system according to claim 1 wherein said emulsifying agent is a surfactant having an HLB value of about 1 to about 20 selected.

5. The hydrophobic pharmaceutical delivery system according to claim 4 wherein said surfactant is selected from the group consisting of reaction products of natural or hydrogenated vegetable oils, polyoxyethylene glycolated, natural or hydrogenated vegetable oils and natural or hydrogenated castor oils.

6. The hydrophobic pharmaceutical delivery system according to claim 1 further comprising pharmaceutically acceptable fillers and excipients.

7. The hydrophobic pharmaceutical delivery system according to claim 1 being encapsulated in a gelatin capsule.

8. The hydrophobic pharmaceutical delivery system according to claim 7 wherein said gelatin capsule is enteric coated.

9. The hydrophobic pharmaceutical delivery system according to claim 8 wherein said enteric coating contains a pharmaceutically acceptable dye.

10. The hydrophobic pharmaceutical delivery system according to claim 1 wherein said pharmaceutically acceptable lipid and said emulsifying agent form a micro-emulsion containing said pharmaceutical agent.

11. The hydrophobic pharmaceutical delivery system according to claim 1 wherein said pharmaceutically acceptable lipid and said emulsifying agent form a micro-emulsion containing said pharmaceutical agent allowing said pharmaceutical agent to be solubilized in aqueous media providing a sustained released drug delivery system.

12. A hydrophobic pharmaceutical delivery system in a gelatin capsule comprising: an active pharmaceutical agent from about 40 to about 80 w/w %; said active pharmaceutical agent is in an admixture with about 20 to about 50 % of a pharmaceutically acceptable lipid; a gelatin capsule; and an emulsifying agent.

13. The hydrophobic pharmaceutical delivery system in a gelatin capsule, wherein said capsule is enteric coated.

14. The hydrophobic pharmaceutical delivery system in a gelatin capsule, wherein said pharmaceutically acceptable lipid and said emulsifying agent form a micro-emulsion containing said pharmaceutical agent allowing said pharmaceutical agent to be solubilized in aqueous media providing a sustained released drug delivery system.

15. A hydrophobic pharmaceutical delivery system in a gelatin capsule comprising: an active pharmaceutical agent from about 40 to about 80 w/w %; and said active pharmaceutical agent is in an admixture with about 20 to about 50 % of a pharmaceutically acceptable lipid.

16. The hydrophobic pharmaceutical delivery system according to claim 15 wherein said pharmaceutical agent is selected from the group consisting of valproic acid , sodium valproate , valpromide, 2-propylpentanol-di-n-propylacetate, glycerol tri- dipropylacetate and di sodium valproate.