Hydroxycitric acid compounds and capsule liquid delivery

Abstract

A capsule oral delivery system is disclosed. The system includes an outer capsule completely enclosing an inner content, or a hard shell comprised of hydroxypropyl methylcellulose (HPMC) enclosing the content. A liquid formulation forming the inner content of the outer capsule is comprised of a hydroxycitric acid (HCA) salt, water, and glycerol, with the HCA being completely dissolved in the water and glycerol which may be the only components present in the capsule, which may be administered to a patient in a method of treatment to cause weight loss when repeatedly administered.

Claims

1. A gelatin capsule oral delivery system, comprising: an outer capsule comprised of gelatin completely enclosing an inner content; a liquid formulation forming the inner content of the outer capsule, the formulation consisting essentially of a salt of hydroxycitric acid (HCA), water, and glycerol, whereby the HCA salt is completely dissolved in the water and glycerol; wherein the liquid formulation is prepared by mixing glycerol in water wherein the glycerol is present in an amount of about 1 to 3 parts by volume and the water is present in an amount of about 3 to 1 parts by volume to create a solution; dissolving hydroxycitrate salt in the solution wherein the hydroxycitrate salt is present in a concentration ranging from about 1.1 to 1.7 molar dosage.

2. The gelatin capsule oral delivery system of claim 1 wherein the hydroxycitrate salt is a stable hydroxycitrate salt selected from a group consisting of sodium, potassium, potassium-magnesium or magnesium hydroxycitrate; double- or triple-metal salts based on the counter ions selected from the group consisting of magnesium, potassium and sodium; and any workable combination thereof.

3. The gelatin capsule oral delivery system of claim 2, wherein the hydroxycitrate salt is a potassium-magnesium salt of ( )-hydroxycitric acid and is present in an amount of 750 mg.

4. A hydroxypropyl methylcellulose capsule oral delivery system, comprising: an outer capsule comprised of hydroxypropyl methylcellulose completely enclosing an inner content; a liquid formulation forming the inner content of the outer capsule, the formulation consisting essentially of a potassium-magnesium salt of hydroxycitric acid (HCA), water, and glycerol, whereby the HCA salt is completely dissolved in the water and glycerol; wherein the liquid formulation is prepared by mixing glycerol in water wherein the glycerol is present in an amount of about 1 to 3 parts by volume and the water is present in an amount of about 3 to 1 parts by volume to create a solution; dissolving hydroxycitrate salt in the solution wherein the hydroxycitrate salt is present in a concentration ranging from about 1.1 to 1.7 molar dosage.

5. The hydroxypropyl methylcellulose capsule oral delivery system of claim 4 wherein the hydroxycitrate salt is a stable hydroxycitrate salt selected from a group consisting of sodium, potassium, potassium-magnesium or magnesium hydroxycitrate; double- or triple-metal salts based on the counter ions selected from the group consisting of magnesium, potassium and sodium; and any workable combination thereof.

6. The hydroxypropyl methylcellulose capsule oral delivery system of claim 4, wherein the hydroxycitrate salt is a potassium-magnesium salt of ( )-hydroxycitric acid.

Description

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) Before the present HCA oral delivery formulations are described, it is to be understood that this invention is not limited to particular formulation described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

(2) Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

(3) Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. It is understood that the present disclosure supercedes any disclosure of an incorporated publication to the extent there is a contradiction.

(4) It must be noted that as used herein and in the appended claims, the singular forms a, an, and the include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a capsule includes a plurality of such capsules and reference to the HPMC includes reference to one or more biocompatible equivalents thereof known to those skilled in the art, and so forth.

(5) The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

(6) Various salts of ()-hydroxycitric acid (calcium, magnesium, potassium, sodium and mixtures of these) have been available commercially for several years. A base formula that can be scaled with appropriate adjustments and used in deliveries such as soft gelatin capsules, liquid-filled hard gelatin capsules and other formats involves only three ingredients: pure potassium-magnesium HCA (best at approximately 69.7% HCA), glycerol and purified water. Another transition metal, such as zinc, can replace magnesium and be prepared in the same manner. Likewise, sodium is roughly interchangeable for potassium. Calcium-containing salts, such as potassium-calcium HCA, can be prepared, but require additional steps and larger volumes due to the poorer solubility of calcium compared with magnesium. Impure salts containing residual gums, fibers, pectins and protein present significant challenges and may not be suitable for preparation. The capsule composition represents another issue. Animal gelatin capsules exhibit a poor tolerance for glycerin-based formulations and are challenged by the hygroscopic characteristics of soluble HCA salts that have been pre-solubilized. Capsule should consist of hydroxypropyl methylcellulose (HPMC) or similar materials, such as seaweed derived alternatives.

(7) These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the gelatin capsule system as more fully described below.

(8) The present disclosure provides a formulation for use in hard or soft capsules, such that capsules filled with the formulation can be prepared and stored without significant degradation, erosion, swelling or dissolution of the capsule shell during the acceptable shelf-life of the filled capsule. For example, the capsules of the invention can be filled with the liquid solution of a highly concentrated salt of hydroxycitric acid and undergo 5% or less degradation over a period of 6 months or more, or 12 months or more and exhibit 5% or less capsule degradation. Any shell forming material suitable for use in hard or soft shell capsules or the encapsulation of a fill formulation can be used in the present invention. In some instances, a capsule includes a liquid drug-containing fill composition enclosed within a capsule shell. The term shell as used herein is taken to mean the shell of a capsule dosage form or the encasement or encapsulation material used to encapsulate formulations and fill compositions.

(9) The fill composition or liquid formulation may be encased by two types of capsules: hard shell capsules and soft shell capsules. Hard shell capsules and soft shell capsules differ in their thickness, amount of cross-linking, rigidity, composition, shape and other ways. Accordingly, a formulation suitable for filling a soft shell capsule might not be suitable for filling a hard shell capsule and vice versa. In some instances, a capsule may contain another small capsule or a tablet along with granules. The granules may be made up of beads or other forms, which may contain more than one type of drug molecules, and specifically the various aqueous formulations of hydroxycitric acid salts as described herein. This way, more than one type of drug may be combined in the same capsule. In some instances, all the drugs reside in the capsule core and there is no drug in the capsule shell composition.

(10) There are two basic embodiments to the invention with one being a gelatin capsule and the other being a hard shell capsule. The liquid formulation of HCA can be used to fill a hard shell capsule. Gelatin soft capsules can be formed around the liquid HCA formulation.

(11) In some instances, the capsule shell for use in the subject systems and methods is a hard capsule shell. The hard capsule shell retains its shape and it is dry in nature. In some instances, there is nothing inside core portion of the capsule shell as the capsule shell may be filled with a liquid fill composition. The capsule shell may be prepared using a film-forming composition/matrix. The hard capsule shell includes two partsa body in the core of which holds the contents of the dosage form, such as, powders/granules/beads/pellets/a mini-tablet/a mini-capsule/liquid formulations and a cap, which fits on the body of the capsule shell and acts as a cover (U.S. Pat. Nos. 4,510,168 and 4,532,881). Apart from the main constituent of the capsule shell being gelatin or polymeric in nature, the shell also contains other excipients such as plasticizers (e.g., polyethylene glycol, sorbitol, glycerol), stabilizers (antimicrobial and antioxidants), colorants (FD&C colors, titanium dioxide, natural dyes including riboflavin, carotenes, turmeric and caramel) and sequestering agents (citric acid, sodium citrate, and ethylenediaminetetraacetic acid). The hard capsule shells may be purchased from capsule suppliers.

(12) There are various sizes of hard capsule shells available ranging from sizes 000 to 5 (higher the number, smaller is the dose volume), the most commonly used are sizes 0 and 1. The fill weight of granules having a density of 0.7 g/mL is 475 mg and 350 mg for size 0 and 1 capsules, respectively. Size 000 capsules can contain 960 mg of core material loaded with medicament. The average weights of size 1 and 0 empty hard gelatin capsule shell are 76 mg and 96 mg, respectively.

(13) A range of different capsule sizes can be used for both the gelatin and hard capsules used in connection with the invention. The capsules can contain any desired amount of the liquid formulation of HCA, and may for example be designed such that the capsule holds 100 mg to 1000 mg of HCA, or 200 mg to 800 mg HCA, or approximately 500 mg HCA, 20%, 10% or 5%.

(14) In treating a patient, the patient may be dosed with one or more capsules at each dosing event. The dosing may be once a day, twice a day, three times a day or more. The total per day dosing may range over any desired range based on the needs of the patient and can be, for example, from 100 mg per day to 5000 mg per day of HCA.

(15) In one embodiment, the dosage is in a range of from 3000 mg to 4500 mg per day. The dosage is delivered with capsules which comprise 750 mg of HCA salt per capsule. Those capsules may be administered in the amount of 4 to 8 capsules per day or 6 capsules per day providing a dosage of about 4.5 grams per day of HCA salt to the patient in order to effectively induce weight loss.

(16) One skilled in the art of formulation will determine the stability of the drug in the capsule shell composition during manufacture and storage.

(17) In certain embodiments, the polymers that can be used in making empty, hard capsule shells can be divided into the following groups: 1) Cellulose- or cellulose compounds, which include, but are not limited to, cellulose, cellulose ether, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl vcellulose, carboxymethyl cellulose, cellulose acetate phthalate, 2) starch-based compounds, which include, but not limited to hydroxyethyl starch, hydroxypropyl starch, hydroxyethyl methyl starch, 3) carrageenans-kappa and iota, 4) Acrylate compounds, which include, but not limited to, polyacrylate, polymethylacrylate, poly(acrylate-methylacrylate), poly(methylacrylate-methyl methacrylate), 5) polyolefins, which include, but limited to, polyvinyl chloride, polyvinyl alcohol, and polyvinyl acetate and 6) pullulan (a polysaccharide polymer consisting of maltotriose units). The empty, hard capsule shell can also be a laminate where the drug-loaded layer is either inner or outer. The non-drug loaded layer can have a function such as, an enteric coated layer or a layer to control drug diffusion as a result of swelling. In some instances, materials suitable for the preparation of the capsule shell include but are not limited to gelatin, starch, animal gelatin, agar, fish (piscine) gelatin or a combination thereof. Essentially any material known to those of ordinary skill in the art as being for the preparation of capsule shell can be used in a capsule according to the invention.

(18) In some instances, empty hard shell capsules may be produced by the following methods: pin dip-coating or heat-melting. A liquid mass is produced by dissolving the capsule compositions in a solvent system or by melting at an appropriate temperature. In the pin dip-method, a plurality of pins maintained at a certain temperature dip in the solution and is withdrawn at a pre-determined rate while spinning. The pins coated with capsule composition are then dried at a gradual rate at a suitable temperature. The body and cap of the capsules are separated from the pins and then trimmed to an exact length. The method has been employed to prepare the body and cap of the capsules. The body and cap are joined together and a logo is printed, if necessary. U.S. Pat. No. 2,526,683 discloses a process for preparing methyl cellulose medicinal capsules by a dip coating process. In the heat-melting method, the hard shell or capsule may be formed by heating a capsule forming composition (preferably in powdery form) in a mold, followed by inserting a pestle into the mold to coat the melted capsule forming composition onto the pestle. The hard capsule shell thus formed, after hardened and dried, is removed from the pestle.

(19) A hard capsule dosage form may be manufactured by filling the core of the hard capsule shell with powders, granules, beads, pellets, a tablet, another capsule, or a liquid fill composition. The fill composition, which may be a water-containing composition, can be a gel, syrup, fluid, semi-solid, solid, suspension, emulsion, paste, or glassy material. In some instances, the capsule dosage form includes a hard hydroxypropyl methylcellulose capsule shell and a liquid formulation including a potassium-magnesium salt of hydroxycitric acid (HCA), water, and glycerol, whereby the HCA salt is completely dissolved in the water and glycerol. The hard shell capsule dosage form may be filled with a liquid formulation and sealed by any suitable manual, semi-automatic, or automatic filling machine and equipment known in the art. Suitable machines for use in filling hard capsules may include dosator machines and dosing-disc machines. The filling of the hard shell capsule may be performed by a capsule filling machine for liquid filling of the type available, for example, from Holfiger and Kars, Zanasi Nigris, Parke-Davis and Co., Eli Lilly and Co., Robert Bosch Corp., among others. The hard shell capsules are generally sealed by one of several methods. The filled capsule may be sprayed with a water alcohol mixture to seal the cap to the body of the container. Alternatively, the cap may be sealed to the body of the container by a bonding process, which entails passing the cap over a revolving wheel immersed in a water gelatin or a cellulose bath and then passing the capsule through a drying chamber to seal the gap between the cap and the body of the capsule with dried gelatin or cellulose. The bonding is generally performed on commercially available machines.

EXAMPLES

(20) The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

(21) Dissolving HCA

(22) In order to produce the most effective capsules of the invention, it is preferable to obtain a relatively high concentration of HCA salt inside the capsules. In one embodiment, this is best obtained by first mixing the glycerol in water. The amount of water and glycerol mixed together are important to obtaining preferred results. The glycerol is present in an amount of about 1 to 3 parts by volume relative to about 1 to 3 parts by volume of water in order to create a desired solution. It may be desirable to include larger amounts of water such as 1.5, 2, or 3 parts of water by volume, relative to 1 part of glycerol. After the solution is obtained, the HCA salt is dissolved in the solution of water and glycerol to obtain high concentration of the HCA salt. The concentration can range from about 1.1 to 1.7 molar and the salt may be any pharmaceutically acceptable salt but is preferably potassium-magnesium salt of HCA.

(23) With respect to each of the examples below, the amounts can vary 20%, 10%, 5%, or 1%.

Example 1

(24) TABLE-US-00001 Base Formula Amount Item # Ingredient per Capsule (mg/capsule) 1 Potassium-Magnesium 750 HCA Salt 2 Glycerol (25% in ~1 mL Purified Water

(25) Batch size will be determined by equipment and the number of capsules desire.

(26) A. Blend glycerol with purified water until dissolved completely.

(27) B. Dissolve the potassium-magnesium hydroxycitrate into the glycerol/water component.

(28) C. The resulting should be quite thick; viscosity can be varied as required by altering the amount of glycerol/water used. Soft gelatin capsules can be formed in the normal fashion and liquid-filled hard shells filled.

(29) (Optional) in this example as well as others, due to viscosity issues, it may be necessary for filling a hydroxypropyl methylcellulose hard capsule to add a small amount of a monoterpene, such as limonene, to the fill material inside of the capsule. Those skilled in the art will adjust the amount of the monoterpene as needed based on nozzle size and filling speed desired. Although the amount can vary, it may be less than 10% by volume of the total volume of the filling, 5% or less, or 1% or less.

Example 2

(30) TABLE-US-00002 Base Formula Amount Item # Ingredient per Capsule (mg/capsule) 1 Sodium HCA Salt 600 2 Glycerol (25% in ~1 mL Purified Water

(31) Batch size will be determined by equipment and the number of capsules desire.

(32) A. Blend glycerol with purified water until dissolved completely.

(33) B. Dissolve the sodium hydroxycitrate into the glycerol/water component.

(34) C. The resulting should be quite thick; viscosity can be varied as required by altering the amount of glycerol/water used. Soft gelatin capsules can be formed in the normal fashion and liquid-filled hard shells filled.

Example 3

(35) TABLE-US-00003 Base Formula Amount Item # Ingredient per Capsule (mg/capsule) 1 Potassium HCA Salt 700 2 Glycerol (25% in ~1 mL Purified Water

(36) Batch size will be determined by equipment and the number of capsules desire.

(37) A. Blend glycerol with purified water until dissolved completely.

(38) B. Dissolve the potassium hydroxycitrate into the glycerol/water component.

(39) C. The resulting should be quite thick; viscosity can be varied as required by altering the amount of glycerol/water used. Soft gelatin capsules can be formed in the normal fashion and liquid-filled hard shells filled.

Example 4

(40) TABLE-US-00004 Base Formula Amount Item # Ingredient per Capsule (mg/capsule) 1 Magnesium HCA Salt 800 2 Glycerol (25% in ~1 mL Purified Water

(41) Batch size will be determined by equipment and the number of capsules desire.

(42) A. Blend glycerol with purified water until dissolved completely.

(43) B. Dissolve the magnesium hydroxycitrate into the glycerol/water component.

(44) C. The resulting should be quite thick; viscosity can be varied as required by altering the amount of glycerol/water used. Soft gelatin capsules can be formed in the normal fashion and liquid-filled hard shells filled.

Example 5

A Confectionery Formulation

(45) The HCA combination of any of Examples 1-4 readily can be incorporated into various confections based on centers or cores. Experimentally, the combination is easily contained in centers including sugars and alcohol sugars such as sucrose, maltose, trehalose, isomaltose, sorbitol, xylitol and so forth. (Gums, pectins and similar binders, however, are to be avoided.) The core must be surrounded by a barrier against moisture, but that barrier should not consist of items that dissolve easily in water-glycerol mixtures. The solution is initially to apply coatings of sugar or polyols to the core by means known to those skilled in the art. Subsequently, a second coating of a fat-based or waxy edible, such as chocolate (or variations such as chocolate and tea extracts), is applied to complete the process with a moisture barrier. The range of centers possible is limited only by the skill and art of the flavor master. HCA has been shown to dramatically slow the crossing of glucose from the gut into the blood, hence there is little fear of inducing blood sugar spikes with these combinations.

CONCLUSION

(46) ()-Hydroxycitrate presents special challenges to delivery by means of soft gelatin capsules and liquid-filled hard shell capsules. A desirable delivery for HCA includes stability/non-lactone formation, avoidance of agents that bind the compound and introduce food effect issues, and some form of pre-solubilization allowing rapid and complete distribution into the gastro-intestinal system. The Invention overcomes these challenges by means of a water-glycerol carrier leading to the creation of a dense and compact product suitable for encapsulation.

(47) The preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims.