WO1998007413A1

WO1998007413A1 - Delivery of sugar as an active ingredient

Info

Publication number: WO1998007413A1
Application number: PCT/US1997/012380
Authority: WO
Inventors: Richard C. Fuisz
Original assignee: Fuisz Technologies Ltd
Current assignee: Biovail Technologies Ltd
Priority date: 1996-08-19
Filing date: 1997-07-22
Publication date: 1998-02-26
Anticipated expiration: 1999-02-19

Abstract

The present invention includes a method and product for controlled-delivery of sugar as a bio-affecting agent. The invention includes sugar in a physical condition which makes it bio-available to a mammalian host. The sugar is physically associated with a controlled-release system in a manner which provides a pre-selected profile of bio-availability to the host. Preferably the sugar is in the form of shearlite particles, and a convenient product for delivery of the sugar includes confections such as a nutrition bar, and unit dosage forms, e.g., tablets and capsules.

Description

DELIVERY OF SUGAR AS AN ACTIVE INGREDIENT

BACKGROUND OF THE INVENTION

The present invention relates to the art of delivering substances for bio-availability to mammals, especially numans . In particular, the present invention concerns the delivery of sugar as an active ingredient. Carbohydrates constitute one of the primary sources of energy for humans. Generally, carbohydrates make up about 50%- "0% cf the normal nu an αiet. Carbonydrates enter the human biological system as glucose which is a ready precursor to fat and which appears to play an important role as a systemic ingredient m several metabolic pathways. In addition, blood sugar levels play a role in the onset of hunger sensations.

It has been desirable to be able to deliver a source of energy to the human body m a manner which enables the host to utilize the energy as it is made available without unnecessary storage of calories or "bulking up" on carbohydrates. Thus, it would be advantageous to provide a continuous source of energy to tne body, and the muscles m particular over a prolonged period of time, or at a particular point ιr time. The anility to supply energy at pre-selected times anc rates is particularly important when the host is engaged in rigorous physical activity such as sustained athletic events, or when the host is dieting to suppress the onset of hunger. Moreover, it is also important to deliver energy to the oody at a preselected time or rate without creating an instantaneous oversupply, i.e., spike, of glucose level m the blood stream. A reduced level of systemic glucose is believed to contribute to appetite and perceived satiety. Increased glucose utilization appears to activate the neural satiety center anc decrease the activity of the feeding center. For example, U.S. Patent No. 4,210,637 to urtman, et al . discloses a composition and method for suppressing appetite for carbohydrate calories while elevating the level of calories consumed as protein. The composition includes a combination of tryptophan and carbohydrate. Tryptophan increases brain serotonin level. Carbohydrates, such as sucrose, dextrose, starc., fructose, invert sugar, dextnns, and sugar polymers, e.g., polyose, xylitol and mixtures thereof: 1) ..-.crease the level of insulin secretion, and 2) decrease the _evels of other neutral ammo acids normally found in plasma sue:, as leuc e, lsoleuc e, tyros e, phenylala ine, and val e, which compete with tryptophan for uptake in the Dram. Consequently, the level of serotonin in the brain is increased. Thus, when a carbohydrate, e.g., sugar, is administered with tryptophan, the appetite of host is suppressed.

Furthermore, glucose levels in humans is very important to control the effects of diabetes mellitus. Diabetes patients suffer from a deficiency m insulin, a hormone wnich stimulates glucose uptake by cells. It is important that a diabetic carefully control the level of glucose available in the body. While too much glucose can be harmful to the patient, a low glucose level can also have serious adverse affects including diabetic snock and even death. Delivery of energy to a host at a pre-selected rate and treatment of the conditions described above, require administration of sugar to the host a manner wnich renders glucose available to the hosts biosystem (hereinafter referred to as bio-availability in a carefully regulated pattern. For example, a non-regulated dosage of sugar which creates a spiked profile of glucose bio-availability could create insatiable craving in a host undergoing treatment to suppress appetite, e.g., an obese patient. Moreover, a similar non-regulated dose could cause a patient to fall into a coma. To-date regulated systems for delivering glucose involve structural (i.e., mechanical) and, n some cases, electrical devices. These solutions suffer from undue complexity, unreliability, cost, unsightl ess, and in some cases require invasive surgical techniques for implementation. Thus, a need currently exists for controlled delivery of carbohydrate, especially sugar, to a mammalian host in accordance with a selected profile of bio-availability without the drawbacks of delivery systems currently available or under consideration. It is an object of the present invention to provide, among other objects, a manner which meets r.is need.

S .-IHAKY OF THE INVENTION

The present invention is a method and a product for the controlled delivery of sugar, as a bio-affecting agent, to a mammalian host, especially a human host. The advantage provided by the present invention is that sugar becomes available to the biological system of the host, i.e., bio-available, in accordance with a pre-selected profile.

The present invention requires that sugar, which has been defined more fully hereinbelow, be provided in a physical condition which makes it readily available to the r.cst. Furthermore, a controlled-release system is physically associated with the sugar to provide the pre-selected and predetermined release profile of bio-availability . In its simplest manifestation, the sugar is combined with a sustained release component as a controlled-release system. The present invention encompasses the use of a controlled- release system which can include a component selected from the group consisting of an instantaneous release component, a delayed release component, and a sustained release component. The controlled-release system can also include a ccmoination of each c the components set forth above. These components are described hereinafter in greater detail. In one preferred embodiment of the invention the controlled-release system includes a combination of at least two of the components set forth above. In another preferred embodiment of the present invention, sugar is provided in the form of shearlite particles. Shearlite particles, which can also be referred to as microspheres, has been fully described in co-pending U.S. Application Serial No. 08/330,412 filed October 28, 1994. The advantages of using sugar in the form of shearlite particles is that the particles can be easily manufactured according with the process disclosed in the co-pending application which enables one to produce particles which are highly uniform in size and shape. Such sr.earlite particles can oe efficiently and predictaαly coated to f rm a component of a controlled-release system.

The methods of tne present invention include rendering sjgar oio-availacie to a nost according to a pre-selected release profile. Specific applications include a metnod of maintaining blood sugar levels as well as a method of suppressing appetite. Furthermore, inasmuch as sugar is a very efficient source of energy, the present invention also includes a method for providing energy to a host at a predetermined point n time or over a predetermined period of time in accordance with a pre-selected release profile.

Products of the present invention include, but are not limited to, comestibles, confections such as nutritional bars and unit dosage forms, e.g., capsules, or tablets. As a result of the present invention a product and method of providing sugar as a source of energy and as a systemic ingredient for use in metabolic pathways m the host is conveniently provided. The sugar can be made bio-available in a numoer of ways without the requirement the host to unnecessarily store calories which usually results m a build up of fat in the body. Energy can also be provided without undue peaks and valleys in levels of glucose in the blood stream as is currently common.

Furthermore, as a result of the present invention, complex and unreliable systems and unnecessary techniques for regulating delivery of sugar known to date are eliminated.

For a better understanding of the present invention, together with other and further ob ects, reference is made to the following description, and its scope will be pointed out in tne appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a method for delivering sugar to a mammalian nost, especially a human host, in a controlled manner so that a desired profile of bio-availability can be provided at a predetermined point in time or over a pre-selected period of time. Since, sugar is the active ingredient the present invention, it must be in a physical condition which makes it reaαily bic-availaole tc a mammalian host, especially a human nost .

Anotner element of tne present invention is a controlleo- release system whicn is pnysically associated with the sugar. The pnysicai association between the controlled-release system and sugar the present invention simply means that the controlled-release system and the sugar are coπiDined in such a way as to provide a highly predictable pre-selected release profile of Dio-availability as a result of normal interaction of the bio-system on the sugar/controlled-release system combination.

The controlled-release system of the present invention can include components sαch as an instantaneous release component, a delayed release component, and a sustained release component. Furthermore, the controlled-release system can include a combination of these components to provide the desired release profile of bio-availability. Preferably, the sugar/controlled- release system combination is included in a confection such as a nutrition bar or a oosage form (e.g., a capsule, tablet, or flowable dosage) .

Sugar as used herein means those substances which are based on simple crystalline mono- and di- saccharide structures, i.e., based on C- and C. sugar structures. Such sugars include sucrose, fructose, lactose, maltose, and sugar alcohols such as sorbitol, manmtol, altitcl, etc. Combinations of sugars can also be used. With respect to a preferred embodiment the sugar should be able to be transformed under liquiflash conditions into shearlite particles. A preferred choice of sugar in the present invention is sucrose.

As previously described, the present invention also includes a controlled-release system whicn is combined physically with the sugar to provide a pre-selected release profile of bio-availability to a host, preferably a human host. Controlled-release system is used herein to describe a composition which can include one or more components for making an active ingredient available to the biological system of a host. The controlled-release system can inciuαe an instantaneous release component, a delayed release component, a sustained release component, and combinations thereof.

An instantaneous release component is self-explanatory in that it refers to an ingredient whicn promotes or enhances immediate release to the biosystem of the host. The present invention includes the possibility of transforming sugar to a physical condition which has a unique release profile different from the release pattern of the same sugar without such transformation. The instantaneous release component can be an additional ingredient which enhances dispersion of sugar throughout the bio-system. An example of an instantaneous release component is a surfactant.

A delayed release component s an ingredient which prevents the active ingredient, i.e., sugar, from being made available to the host until some time after initial administration. When administration is oral, the delayed release component prevents release of sugar until some time in the future. Delayed release components include, but are not limited to, polymeric coatmg(s), biodegradable coating(s), etc. A sustained release component is an ingredient, or combination of ingredients, which permits release of active ingredients to the host at a certain level over a period of time. Sustained release can be provided by use of coatings whicn include gels, waxes, fats, emulsifiers, combinations of fats and emulsifiers, polymers, starch, etc., as well as the above in combination with polymeric coating (s) or other biodegradable coatings.

The method of effecting each type of release can be varied. For example, the sugar can be associated physically (which also includes being chemically associated or bound) with one or more of the components set forth above. Alternatively, the active ingredient can be a coated, laminated, encapsulated etc., such as discussed below. Regardless of the method of providing the desired release profile, the present invention contemplates use of one or more of the components descrioed above.

With respect to the sustained release component, the patent and scientific literature is replete with various sustained release (SR) methods and formulations. For common methods of optaining SR systems, see Sustained and Controlled Release Drug Deliver-_, Systems, Robinson, Josepn R., Eo., P? 138-171, 1978, Marcel De er, Inc. New Yor , NY. For example, it is known to fill poi/meric capsules witn a solid particle wnich can, turn, be maoe to re_ease active ingredient according to a known pattern or profile. Such particles can also be made to have more tnan one release profile so that over an extended time the corru-ined release patterns provide a pre-selected profile. Furthermore, heterogeneous matrices, such as, for example, compressed tablets, control the release of active agents either by diffusion, erosion of the matrix cr a combination of both. Other SR systems focus cn the fabrication of laminates of polymeric material ano active agent .vnich are then formed into a sandwich, relying on diffusion or erosion to control release of the active agent. Additionally, it is generally known that heterogeneous dispersions or solutions of active agents water-swellable hydrogel matrices are useful in controlling the release of the agent by slow surface-to-center swelling of tne matrix and subsequent diffusion of tne active agent from the water-swollen part of the matrix.

During dissolution of a controlled-release matrix tablet, the dosage form generally remains as a non-dis tegrat g, slowly eroding entity from which the active agent leacnes out, tnrougn a diffusion controlled process. Conventional SR formulations are generally designed to release their actives over an extended period of time, usually 8-24 hours. Conventional SR formulations use waxes or hydrophilic gums as the primary carriers to prolong the release of the active ingredients. In conventional wax matrix tablet formulations, the active agent is dispersed m the wax matrix in the molten state. Conventional waxes and waxy materials used m pharmaceutical formulations are carnuoa wax, spermaceti wax, candellila wax, cocoa butter, cetosteryl alcohol, beeswax, partially nydrogenated vegetable oils, ceresin, paraffin, myπstyl alcohol, stearyl alcohol, cetyl alcohol and stearic ac d. They are generally used in amounts of about 10 to about 50--- by weight of the total formulation. Hydrophilic gums have also been known to be reasonably effective as SR carriers for both high-ocse and low-dose active agents. Typical hydrophilic gums used as SR carrier materials are acacia, gelatin, tragacanth, veegum, xanthin gum, carooxymethyl cellulose (CMC) , hydroxypropl methyl cellulose iHPMC) , hydroxy propyl cellulose (HPC) and hydroxy ethyl cellulose (HEC) . Generally these materials are present in amounts of about 10 to 50 by weight of the final formulation.

Starch USP (potato or corn) is commonly used as a component m conventional tablet or hard shell capsule formulations. It generally functions in conventional applications as a diluent or as a dis tegrant in oral dosage forms. Starch paste is also often used as a binder in these products. Various modified starcnes, such as carboxymethyl starcn currently marketed under tne trade name Explotab or Pnmojel are used both in tablets and capsules as disintegrating agents. The literature discloses that native and modified starches are useful m promoting rapid release of active agents from solid oral dosage forms, and, tnus, could be used as an instantaneous release component. Additionally, native starch has been used in some instances as a binder to produce granulations of active ingredients. More recently, pregelat ized starch has been reported as being useful as an SR matrix for theophyllme formulations by Herman and Remon, "Modified Starches as Hydrophilic Matrices for Controlled Oral Deliver; III Evaluation of Sustained-Release Theopnyll e Formulations Based on Thermal Modified Starch Matrices Dogs," in International Journal of Pharmaceutics, 63 (1990) 201-205. In sustained release applications several types of modified starch were mixed with anhydrous theophyllme (60:40 W/W) as well as with silicon dioxide (Aerosil 200) and sodium benzoate. In prior papers, (International Journal of Pharmaceutics, volumes 56 (1988) 145-153; 56 (1989) 51-63; and 56 (1989) 65-70) the authors discussed the use of both drum- drying and extrusion of native starches to obtain partial or full pregelat ization.

Polymers useful as coatings in the present invention are those deposited as solution coatings and dispersion coatings wnich can be used to coat particles, including shearlite particles. Flasticizers are also normally included m coth organic solvent systems and aqueous systems. The cresent invention includes tne use of known polymers, plastic zers, dispersions, etc. which can be used in or as coatings for sugar particles.

In general however, processes known in the art for preparing coated particles can be used with the present invention .

As a result of the high uniformity and narrow size distribution, shearlite particles permit the use of substantially less coating materials to produce the intended effect. Thus, with a single complete but thin coat, efficient controlled-release can be effected. This however, does not preclude shearlite particles from being coated with multiple layers of active and controlled release coatings.

In all controlled release technologies it is desirable to be able to incorporate the active ingredient in a single dosage unit to provide the pre-selected release profile without deteriorating the active ingredient. Moreover, tne dosage unit should be able to deliver the active ingredient without interfering with the pre-selected release profile.

In the present invention sugar is the active ingredient which is combined with one or more of the delivery components to provide a host with a pre-selected profile of bio-availability of sugar. The term physically associated is used herein to describe the nature of the combination of sugar and delivery or release component, and tne term includes all features of the relationship between the sugar and the delivery component, e.g., structural, chemical, mechanical, etc. of primary importance is that the combination renders sugar bio-available to the host according to a pre-selected profile.

The profile can be selected to achieve one of many goals. For example, the release of sugar can be engineered to provide a sustained source of readily useable energy; or to participate in the metabolic system(s) which controls appetite to suppress (or even enhance) appetite; or to ensure an acceptable level of blood sugar for a diabetic patient, or to provide a delayed release of sαgar as a useable energy. Other benefits are contemplated and can oe achieved based on the desired elect ve .

In the case of providing a source of energy from tne alimentary tract to augment physical activity, the pre-selected profi-e will require a dosage which is planned based on the t me expected for the human system to digest a substance, e.g., generally not greater than about four (4) hours. If the host is net engaged m strenuous activity, the dosage can oe recucec, or delayed until the energy source is required. For an appetite suppressant the dosage rate can be similarly planned, and, if a co-active ingredient is administered proximally with the sugar, the dosage can De adjusted depending on the desired result. Additional co-active ingredients which are known for use as appetite suppressants include, but are not limited to, tryptophan (especially when used with an msulin-mducmg carbohydrate) , diethylpropion hydrochloride, mazindol, phentermme hydrochloride, fenfluramme hydrochloride (d-fenfluramine and the racemic dl-fenfluramm) , fluoxetme hydrochloride, and phenylpropanolamine hydrochloride. When the host is a diabetic, a sustained sugar release profile can be selected which delivers glucose at an even rate over several hours.

A particularly preferred embodiment of the present invention includes the use of sugar m tne form of shearlite particles. As descπ^ped in co-owned U.S. Patent Application Serial No. 08/330,412, sugar snearlite particles are discrete particles prepared by subjecting a solid sugar feedstock, capable of being transformed to a liquiform tne substantial absence of a dissolving medium, to liquiflash conditions to provide sucstantially unimpeded internal flow. The feeαstoc, thus reduced to unimpeded internal flow, is subsequently separated by natural mass separation of the flowing feedstock in the presence of shear force to form snearlite particles.

Shearlite particles prepared in accordance with the present invention are ideally suited for coating. They have a nighly consistent spheroidal shape and the narrow range of size distribution causing the shearlite particles to flow evenly and easily and to be susceptible to even coating with a minimum

10 a.T.cunt of coating material. Consequently, shearlite particles can oe efficiently coated to obtain a corresponding ccnsistentiy-coated product. liquiflasn conditions are those conditions w ich provide transformation of a solid to a liquid state and then to the solid state (e.g., solid-liquid-solid) instantaneously. By instantaneously is meant less than seconds, preferaoly on the order of fractions of a second, and most preferably on the order of milli-seconds . Thus, certainly the transformation from solid to liquid to solid takes place m a time period of less than five seconds, preferably less than one second, and most preferably less than 0.1 seconds.

During this rapid transition, shear forces can act on the material to separate the feedstock while liquiform. Thus, liquiflash conditions are the combination of temperature and force which induce the sugar feedstock to flow and re-solidify into a changed shape as it is being separated by the action of shear force. In preferred embodiments the size and the new shape of the particles are highly consistent. The shape is substantially spheroidal and the size distribution is very limited with only minor variations.

The discrete particles produced are preferably microspheres, which as used herein, means not greater than about 500 F , more preferably not greater than about 400 F , and most preferably not greater than about 300 Fm. In the preferred method of the present invention the liquiflash conditions are provided by a spinning head having a heated peripheral barrier with exit openings provided therethrough for passage of feedstock flowing under centrifugal force as described in U.S. Patent Application Serial No. 08/330,412, filed October 28, 1994 and hereby incorporated by reference.

According to the present invention the controlled release sugar can then be utilized to form numerous comestibles, including nutritional bars and the like. Additional ways of administering the active ingredient of the present invention to mammalian hosts are also contemplated.

11 EXAMPLES

EXAMPLE I

Sucrose Spheres

Sustained release sugar microspheres can be prepared by forming sugar particles or microspheres (shearlite particles), as taught and described in U.S. Patent Application No. 08/330,412. The sugar spheres (or plain sugar particles) may then be coated with coating materials such as Eudragit⁷ E100

(7.5% ethocel} dissolved in a solvent of acetone and methanol in a ratio of 5:1.

EXAMPLE II Coated Sugar Microspheres

A mixture of various coated, sustained release sugar particles (including coated shearlite particles) are combined in amounts such the release profile in the host body is sufficient to provide a sustained, elevated blood sugar level in the subject host (or to conform to a desired release profile) . The mixture of coated sugar particles include measured

(predetermined) amounts of sugar particles which have been coated with different coatings. The different coatings will each provide their own, unique release profile. But when combined in various, predetermined amounts, or manner, the finished mixture will provide the desired release profile throughout the desired period of time.

The coated particles can be administered in any number of known forms, including nutritional bars, tablets, capsules, unit dose, etc.

Additionally, the sugar does not have to be coated. It just has to be made available to elevate, or maintain the host's blood sugar levels when desired. Also, formulations of sustained release sugar could be coated onto a non-sugar bead or rtucrosphere, or even a sugar

(shearlite) particle.

12

Claims

1. A comestible for controlled delivery of sugar as a bio- affect g agent coprismg: sugar m a physical condition which makes it b o- avaixable to a mammalian nost, and a controlleα-release system physically associated witn said sugar to provide a pre-selected release profile of bio- avaiiability to said host.

2. The comestible according to Claim 1 wherein said sugar is the form of shearlite particles and said controlled- release system is coated over said shearlite particles.

3. A method of rendering sugar bio-available to a mammalian host according to a pre-selected profile comprising : administering a combination of sugar n a bio-available condition and a controlled-release system physically associated with said sugar to release said sugar according to said profile.

4. The method according to Claim 3 wherein said sugar is the form of shearlite particles and said controlleα- release system is coated over said shearlite particles.

5. A method of maintaining blood sugar levels in a mammalian host according to a pre-selected profile comprising: administering a combination of sugar a bio-available condition and a controlled-release system physically associated with said sugar to release said sugar according to said profile.

6. A method of suppressing appetite m a mammalian host comprising : administering a combination of sugar in a Dio-avaiiaole condition and a controlled-release system physically associated with said sugar to release said sugar according to a pre-selected profile which is associated with appetite suppression .

7. A nutrition bar for controlled delivery of sugar as a bio-affecting agent comprising: sugar a physical condition wnich makes t bic- available to a mammalian nost, and a controlled-release system physically associated with said sugar to provide a pre-selected release profile of bio- availability oto said host.

8. A unit dosage for controlled delivery of a sugar as a bio-affecting agent comprising: sugar in a physical condition which makes it bio- available to a mammalian host, and a controlled-release system pnysically associated with said sugar to provide a pre-selecteo release profile of bio- avaiiability to said host.

9. The unit dosage of Claim 8 which is a capsule.

10. The unit dosage of Claim 8 which is a tablet.