DESC:
HARD CANDY COMPOSITIONS OF XYLITOL

FIELD OF THE INVENTION
The present invention relates to hard candy compositions of xylitol. The invention also provides the processes for the preparation of such compositions. Furthermore, the invention relates to the use of said compositions to quench thirst in patients associated with chronic kidney diseases (CKD), End-Stage Renal Disease (ESRD) or oncology supportive care treatment.

BACKGROUND OF THE INVENTION
CKD and ESRD patients have a limit to the amount of fluids they can ingest due to impairment in kidney function and inability to urinate, resulting in severe dry mouth as they cannot take enough water. So, the use of chewing gum and hard candies which will actually make their mouth produce more saliva, which in turn makes them less thirsty is quite popular, rather than keeping the patient thirsty.

Sugar or sucrose, is probably the most important ingredient in the confectionery industry. Sucrose is used to provide sweetness and the body in confectionery products and its properties also govern the textural attributes of such products. Although a wide variety of alternative sweeteners are commercially available, it is generally considered that sucrose is the optimum sweetener with regard to taste profile and technological properties. However, sucrose has been implicated as a contributory factor in many diseases, including hypertension, coronary heart disease, arterial sclerosis and dental caries. These health concerns have led health care professionals to analyze the effects of sucrose and its prominent role in the confectionaries.

Xylitol have been used in certain contexts, including chewing gum and hard candies. For example, U.S. Patent No. 4,514,422 (Yang) and 3,422,184 (Patel) disclose the use of xylitol (as well as other sugar alcohols) in sugar-free chewing gums. Sugar-free gums and candies made up of xylitol have the advantage to overcome the above concerns.

The processing of xylitol hard candies has some limitation, due to certain characteristics such as low viscosity and unique crystallization properties, has been difficult to integrate into a shelf stable, an acceptable tasting product which can be efficiently and practically produced on a commercial scale.

Finnish patent publication no. 61265 describes a process in which 10 - 30 % by weight of xylitol powder is added to a xylitol melt and the melt is maintained at a temperature not exceeding xylitol's melting point of 96°C. The melt obtained was poured into moulds and allowed to cool. This known process is not continuous, and is thus not very well suited for industrial production.

Finnish patent application no. 885397 describes a process for preparing candies containing xylitol and sugar alcohols. According to the process, a mixture containing xylitol and maltitol is melted and coarse xylitol powder is added to the melt and from the mixture candies are formed. This process does not lead to a satisfactory end result and the process cannot be used on an industrial scale due to the hygroscopicity of xylitol. The process produces a hygroscopic mixture which is difficult to work. It does not maintain its shape and is a perishable product.

WO91/07100 discloses hard candies compositions comprising xylitol 30-70%, sugar substitutes 70-30% (eg. mannitol, isomalt, lactiol) and a process for preparing these candies through melting at 120-175°C and later cooling at 95-130°C .
US 2008/0161417 discloses rapidly disintegrating xylitol granule composition which is directly compressible into tablet, comprising Xylitol, polyvinyl pyrrolidone and may also comprise Sorbitol and hydroxypropyl methylcellulose and process for preparation. It also discloses that polyvinyl pyrrolidone not only has excellent adhesive effect, but also has a function of rapid disintegration.
Few xylitol based products are available in the form of chewing gums and candies in market. eg. Spry® xylitol products. The use of chewing gums is not suitable for all occasions. Everyone does not want to chew gum and consider it inconvenient, further chewing requires relatively effective chewing properties, etc. The other commercial product available is SparX®, the first product offered under Xlear's sugarfree candy line, fine & dandy candy. SparX are naturally fruit flavored, bite size candies sweetened exclusively with 100% pure xylitol. Also, Dr. John’s offers delicious sugarless hard candy with xylitol which has a low glycemic index, thus offers oral health benefits.

The xylitol compositions available in the art are not effective enough to provide desired thirst quenching relief to patients due to their fast disintegration and lesser residence time in mouth. Therefore, there is a need of xylitol hard candies compositions which are shelf stable, acceptable tasting, can be efficiently and practically produced on a commercial scale and have long residence time in mouth. The inventors of the present invention found that a hard candy compositions of xylitol comprising sugar substitute and one or more polymer having longer residence time in mouth or pharynx and hence longer contact time with mucosa, offering the desired thirst quenching relief to patients.

SUMMARY OF THE INVENTION
The present invention relates to hard candy compositions of xylitol. The invention also provides the processes for the preparation of such compositions. Furthermore, the invention relates to the use of said compositions to quench thirst in patients associated with chronic kidney diseases (CKD), End-Stage Renal Disease (ESRD) or oncology supportive care treatment.

In one aspect, the present specification relates to hard candy compositions comprising:
(i) xylitol;
(ii) one or more sugar substitute;
(iii) one or more polymer; and
(iv) one or more excipients.

In another aspect, the present specification relates to hard candy compositions comprising:
(i) xylitol;
(ii) isomalt;
(iii) one or more polymer; and
(iv) one or more excipients.

In yet another aspect, the present specification relates to hard candy compositions comprising:
(i) xylitol;
(ii) one or more sugar substitute;
(iii) one or more polymer; and
(iv) one or more excipients;
wherein the composition has residence time of more than 20 minutes in the oral cavity upon administration to a subject in need thereof.

In yet another aspect, the present specification relates to hard candy compositions comprising:
(i) xylitol;
(ii) one or more sugar substitute;
(iii) one or more polymer; and
(iv) one or more excipients;
wherein the composition has residence time of more than 15 minutes in the oral cavity upon administration to a subject in need thereof.

In other aspect, the invention is designed to achieve a lower glycemic load, wherein the glycemic load is not more than 10.

In other aspect, the invention relates to the use of said compositions for quenching thirst in patients associated with chronic kidney diseases (CKD), End-Stage Renal Disease (ESRD) or oncology supportive care treatment.

In yet another aspect, the invention relates to the use of said compositions for quenching thirst in cancer patients, especially those having restriction on fluid intake as a supportive care treatment.

DESCRIPTION OF THE INVENTION
The present invention relates to hard candy compositions of xylitol. The invention also provides the processes for the preparation of such compositions. Furthermore, the invention relates to the use of said compositions to quench thirst in patients associated with chronic kidney diseases (CKD), End-Stage Renal Disease (ESRD) or oncology supportive care treatment.

In one embodiment, the present specification relates to hard candy compositions comprising:
(i) xylitol;
(ii) one or more sugar substitute;
(iii) one or more polymer; and
(iv) one or more excipients.

In another embodiment, the present specification relates to hard candy compositions comprising:
(i) xylitol;
(ii) isomalt;
(iii) one or more polymer; and
(iv) one or more excipients.

In yet another embodiment, the present specification relates to hard candy compositions comprising:
(i) xylitol;
(ii) one or more sugar substitute;
(iii) one or more polymer; and
(iv) one or more excipients;
wherein the composition has residence time of more than 20 minutes in the oral cavity upon administration to a subject in need thereof.

In yet another embodiment, the present specification relates to hard candy compositions comprising:
(i) xylitol;
(ii) one or more sugar substitute;
(iii) one or more polymer; and
(iv) one or more excipients;
wherein the composition has residence time of more than 15 minutes in the oral cavity upon administration to a subject in need thereof.

In another embodiment, the present specification relates to hard candy compositions comprising:
(i) 25-50% w/w xylitol;
(ii) 15-60% w/w isomalt;
(iii) 5-15% w/w polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer; and
(iv) 1-50% w/w one or more excipients;
wherein the composition has residence time of more than 15 minutes in the oral cavity upon administration to a subject in need thereof.

In an embodiment, the present specification relates to hard candy compositions comprising:
(i) xylitol;
(ii) isomalt;
(iii) hydroxyl propyl cellulose; and
(iv) one or more excipients;
wherein the composition has residence time of more than 15 minutes in the oral cavity upon administration to a subject in need thereof.

In another embodiment, the present specification relates to hard candy compositions comprising:
(i) 25-50% w/w xylitol;
(ii) 15-60% w/w isomalt;
(iii) 1-15% w/w hydroxyl propyl cellulose; and
(iv) 1-50% w/w one or more excipients;
wherein the composition has residence time of more than 15 minutes in the oral cavity upon administration to a subject in need thereof.

In yet another embodiment, the invention is designed to achieve a lower glycemic load, wherein the glycemic load is not more than 10.

In yet another embodiment, the invention relates to the use of said compositions for quenching thirst in patients associated with chronic kidney diseases (CKD) End-Stage Renal Disease (ESRD) or oncology supportive care treatment.

The term “Hard candy composition or formulation” as used herein, refers to a solid oral lozenges dosage form intended to be sucked and held in the mouth or pharynx. Hard candy can be of various shapes, the most common being the flat, circular, octagonal, and biconvex forms. The terms formulation or composition are used interchangeably herein.

The term “xylitol” as used herein is refers to naturally occurring five carbon sugar alcohol. It occurs naturally in many fruits and vegetables and is produced by the human body during normal metabolism. It is a sweet crystalline product, white in color, odorless and soluble in water. In crystalline form, it quickly dissolves in the mouth. It has a negative heat of dissolution, and thereby produces an agreeable refreshing or cooling effect in the mouth. The concentration of xylitol employed in the present specification is from 25-50% w/w, e.g. 25-30%, 30-35%, 35-40%, 40-45%, 45-50% w/w by weight of the composition.

The term “sugar substitute” as used herein refers to a type of sugar alcohol. Sugar substitute used herein are selected from the group comprising isomalt, sorbitol, mannitol, erythritol, D-tagatose, lactitol, maltitol and sucralose or combination thereof. The concentration of sugar substitute employed in the present specification is from 15-60% w/w, e.g. 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60% w/w by weight of the composition.

The term “polymer” as used herein refers to is a large molecule, or macromolecule, composed of many repeated subunits. The range of polymer employed in the present specification is from 1-15% w/w e.g. 1-5%, 5-10%, 10-15% w/w by weight of the composition. The polymer used herein are selected from the group comprising homopolymers and copolymers of N-vinyl lactams, especially homopolymers and copolymers of N-vinyl pyrrolidone, e.g., the homopolymer polyvinylpyrrolidone (PVP or povidone) and copolymers such as those comprising monomers of N-vinyl pyrrolidone and vinyl acetate (copovidone) or N-vinyl pyrrolidone and vinyl propionate; cellulose esters and cellulose ethers, in particular methylcellulose, ethylcellulose, (hydroxyalkyl) celluloses such as hydroxypropylcellulose, (hydroxyalkyl)alkyl-celluloses such as hydroxypropylmethylcellulose (HPMC or hypromellose), cellulose phthalates and succinates such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropylmethylcellulose succinate (HPMC-S) and hydroxypropylmethylcellulose acetate succinate (HPMC-AS); high molecular weight polyalkylene oxides such as polyethylene oxides (PEGs or PEOs) and copolymers of ethylene oxide and propylene oxide (poloxamers); polyacrylates and polymethacrylates such as methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl methacrylate copolymers, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymers, poly(hydroxyalkyl acrylates) and poly(hydroxyalkyl methacrylates); polyacrylamides; vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, polyvinyl acetate, polyvinyl alcohol and partially hydrolyzed polyvinyl acetate (also referred to as partially saponified polyvinyl alcohol); graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., Soluplus™ of BASF or equivalent product); oligo and polysaccharides such as carrageenans, galactomannans and xanthan gum or combinations thereof.

The composition according to the present specification optionally comprises one or more excipients used in the cosmetics or pharmaceutical field, such as diluent, binder, lubricant, artificial flavor and sweetener. Needless to say, a person skilled in the art will take care to select this or these optional excipient(s), and/or the amount thereof. These excipients may be present in the composition in a range from 1-50% w/w by weight of the composition.

The diluents used herein are selected from the group comprising lactose, e.g., lactose monohydrate, directly compressible lactose, lactose anhydrous, and spray dried lactose; starch, e.g., pregelatinized starch; microcrystalline cellulose, e.g., microcrystalline cellulose PH 112, microcrystalline cellulose PH 101, and microcrystalline cellulose PH 102; Polyethylene Glycol; dicalcium phosphate; calcium sulfate; calcium carbonate and combinations thereof.

The binders used herein are selected from the group comprising acacia; tragacanth; xanthan gum; sodium alginate; corn syrup; sugar syrup; gelatin; polyvinylpyrrolidone; povidone; copovidone; propylene glycol; polyvinyl alcohol; methacrylates; carboxyvinyl polymers, e.g., carbomers and combinations thereof.

The lubricants used herein are selected from the group comprising magnesium stearate, zinc stearate, calcium stearate, stearic acid, PEG and combinations thereof.

The flavorants used herein are selected from the group comprising menthol flavor; citrus flavor e.g., orange flavor, lemon flavor; berry flavors; mint flavor; Vanilla flavor; stone fruits flavor; grape flavor; maple flavor; honey flavor; cherry flavor; rasp berry flavor; straw berry flavor; spice flavor; maple flavor; melon flavor; raspberry flavor; mixed citrus flavor; mixed fruit flavor; Licorice flavor; anise coffee flavor; chocolate flavor; cherry flavor; peach flavor; raspberry flavor; nut flavor; fennel flavor and combinations thereof.

The term “long residence time” as used herein, refers to a lozenge formulation having residence time more than 20 minutes once kept in mouth and the formulation is slowly dissolving and having longer contact time with mucosa which has a thirst quenching effect in patients with kidney diseases (CKD), End-Stage Renal Disease (ESRD) and oncology supportive care treatment. The residence time of the xylitol compositions according to present invention is preferably in the range of 15 - 30 minutes, more preferably 20-25 minutes in the oral cavity upon administration to a subject in need thereof.

The hard candy compositions of the present invention exhibits a low “glycemic load”. Glycemic load of a serving of food can be calculated as its carbohydrate content measured in grams (g), multiplied by the food's glycemic index (GI), and divided by 100. The term “glycemic index” as used herein refers to a number associated with a pharmaceutical formulation which measures the impact of the formulation on blood sugar level.
The formulations can be divided into the following way according to their glycemic load (GL) values:
Low GL Medium GL High GL
0-10 11-19 20 or greater

The formulation as described herein has a low glycemic load and hence it is a sugar free and calorie free formulation and is suitable for diabetic patients.

In another embodiment, the invention is designed to achieve a lower glycemic load, wherein the glycemic load is not more than 10, preferably not more than 5, more preferably not more than 1.

In yet another aspect, the present specification provides a processes for the preparation of the hard candies composition of xylitol. The process for the preparation may be any conventional suitable process e.g. direct compression, dry granulation, wet granulation, melt extrusion.

The term “direct compression” as used herein refers to a process generally described in the art, by which powder blends of the active ingredient and suitable excipients are compressed directly in a die cavity and form into a firm compact.

The term “dry granulation” as used herein, refers to a process generally described in the art, which involves the step of compressing premixed powders and reducing the compressed material to the proper size for tablet granulation purposes. Another dry granulation procedure is slugging, in which slugs or large tablets are compressed and are subsequently grounded to the desired granulation characteristics.

The term “wet granulation” as used herein, refers to a process generally described in the art, in which a granulating fluid is added to powder in a vessel equipped with any type of agitation that will produce agglomeration or granules. The granulating fluid contains a solvent which can be removed by drying, and should be non-toxic. Typical solvents include water, ethanol and isopropanol and methylene chloride either alone or in combination. The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved binder / suspension / gelatinized binder.

The term “hot-melt extrusion” as used herein, refers to a process generally described in the art, which involves the step of blending pre-determined ratio of drug and polymer and feeding the blend into a twin screw extruder with a controlled temperature. The extrudates are collected, processed, mixed with suitable excipients and compressed in to a tablet or filled into a hard gelatin capsule. The extrudate pharmaceutical compositions of the present specification may be prepared by conventional twin screw or hot melt extrusion process for oral solid dosage forms.

In one embodiment, the present specification relates to direct compression process for preparing compositions comprising:
(i) 20-50% w/w xylitol;
(ii) 10-50% w/w isomalt;
(iii) 1-15% w/w hydroxyl propyl cellulose; and
(iv) 1-50% w/w one or more excipients;

In another embodiment, the present specification relates to dry granulation process for preparing compositions comprising:
(i) 20-50% w/w xylitol;
(ii) 10-50% w/w isomalt;
(iii) 1-15% w/w hydroxyl propyl cellulose; and
(iv) 1-50% w/w one or more excipients;

In another embodiment, the present specification relates to wet granulation process for preparing compositions comprising:
(i) 20-50% w/w xylitol;
(ii) 10-50% w/w isomalt;
(iii) 1-15% w/w hydroxyl propyl cellulose; and
(iv) 1-50% w/w one or more excipients;

In another embodiment, the present specification relates to hot-melt extrusion process for preparing hard candy compositions comprising:
(i) 25-50% w/w xylitol;
(ii) 15-60% w/w isomalt;
(iii) 5-15% w/w polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer; and
(iv) 1-50% w/w one or more excipients;
wherein the process temperature is in the range of 60-90°C.

The hard candy compositions of the present invention are suitably packed in any conventional blister pack or stick pack or sachet.

While this invention has been described with reference to specific embodiments, the scope of the invention is not limited to these embodiments alone. The invention is further illustrated by the following examples, which are for illustrative purpose only and should not be construed as limiting the scope of the invention in any way.

EXAMPLES
Example 1: Hot melt extrusion
Ingredient Example 1a
Quantity (% w/w) Example 1b
Quantity (% w/w) Example 1c
Quantity (% w/w)
Xylitol 50.00 30.00 30.00
Isomalt 40.00 60.00 60.00
Soluplus 10.00 10.00 10.00
Menthol / Orange 1.00 0.5 0.5
Sucralose - - 1.00
Magnesium stearate 0.20 0.2 0.2
Xylitol compositions according to example 1a, 1b, 1c were prepared by using hot melt extrusion process comprises following steps:
(i) Dry-powder blend of Xylitol and Soluplus was prepared,
(ii) The blend was fed at a controlled rate to a twin screw extruder, using a Gravimetric powder feeder. The extruder has a temperature controller (maintained at 75 – 85 °C) and was equipped with a cylindrical die,
(iii) Extrudates were collected at the die end and milled in to different sizes for direct use or further processing accordingly,
(iv) The milled extrudates were mixed with Isomalt, Gum Acacia, Sucralose, Orange flavor and Magnesium Stearate and a blend was prepared,
(v) The final blend was compressed into a tablet and suitably packed.

Example 2: Direct compression
Ingredient Quantity (mg)
Xylitol 500.00
Isomalt 889.80
Acacia 200.00
Sucralose 16.00
Menthol flavor 10.00
Orange flavour 25.00
Hydroxypropyl cellulose 125.00
Magnesium stearate 16.00
Sodium stearyl fumarate 8.00
Total Weight 1800.00
Xylitol compositions according to example 2 was prepared by using direct compression process comprises following steps:
(i) Xylitol was milled with isomalt, acacia and Hydroxypropyl cellulose and a dry mixture blend was prepared,
(ii) Dry mixture blend of step (i) was sifted and blended with menthol and orange flavors and sucralose,
(iii) Blend of step (ii) was lubricated with magnesium stearate and sodium stearyl fumarate,
(iv) The blend of step (iii) was directly compressing into a compressed tablets. Hardness of the compressed was maintained at a range of 200 N to 400 N; most preferably about 300N.

Example 3: Wet granulation
Ingredient Quantity (mg)
Xylitol 500.00
Isomalt 313.00
Lactose monohydrate (200 M) 500.00
Acacia 200.00
Sucralose 15.00
Menthol flavor 5.00
Orange flavor 16.00
Hydroxypropyl cellulose 75.00
Magnesium stearate 16.00
Total Weight 1640.00
Xylitol compositions according to example 3 was prepared by using wet granulation process comprises following steps:
(i) Xylitol was sifted and mixed with lactose monohydrate, some part of acacia and some part of hydroxypropyl cellulose,
(ii) Granulating fluid was prepared by dissolving or dispersing some other part of acacia in water,
(iii) Material of step (i) was granulated using the granulating fluid of step (ii),
(iv) Kneading was performed after granulation mass of step (iii),
(v) Wetted mass was dried after step (iv),
(vi) Granules were sized after step (v),
(vii) Isomalt, remaining part of acacia, remaining part of hydroxypropyl cellulose, sucralose, menthol and orange flavor were sifted and added to sized granules of step (vi) and blended well until uniformity is achieved,
(viii) Magnesium stearate was added to blend of step (vi) and lubricated and compressed into tablet.
Disintegration time:
The Xylitol compositions were prepared in accordance with examples 1, 2 and 3.The compositions were subjected to disintegration test in USP disintegration apparatus (DT) using water (1000ml) maintained at 37±2°C. The time taken for complete disintegration was noted. The compositions were found to have long residence time in mouth compared to marketed products. The time taken for complete disintegration was noted and compared. The results were shown in Table 1.
Table 1: Disintegration time comparison
Product Disintegration time (min) in USP DT Apparatus
Example 1a 21
Example 1b 20
Example 1c 25
Example 2 24
Example 3 29

Glycemic load:
The glycemic load of the composition prepared according to example 3 was calculated by multiplying individual excipients GI by the number of carbohydrate grams in a serving, and then divide by 100. The results were shown in Table 2. The composition was found having low glycemic load.
Table 2: Glycemic load calculation
Ingredient mg/Lozenge Glycemic
index Carbohydrates/ Serving (g) Glycemic Load per serving
Xylitol 500.00 12 0.5 0.06
Isomalt 313.00 2 0.313 0.0063
Lactose monohydrate 500.00 45 0.5 0.225
Acacia 200.00 0 50 0
Sucralose 15.00 0 0 0
Menthol flavor 5.00 - - 0
Orange flavor 16.00 - - 0
Hydroxypropyl cellulose 75.00 0 0 0
Magnesium stearate 16.00 0 0 0
Total 1640.00 - - 0.29
,CLAIMS:CLAIMS:
1. A hard candy composition comprising:
(i) xylitol;
(ii) one or more sugar substitute;
(iii) one or more polymer; and
(iv) one or more excipients,
wherein the composition has residence time of about 15-25 minutes in the oral cavity upon administration to a subject in need thereof.

2. The composition of claim 1, wherein the one or more sugar substitute are selected from the group comprising isomalt, sorbitol, mannitol, erythritol, D-tagatose, lactitol, maltitol and sucralose or combination thereof.

3. The composition of claim 2, wherein the sugar substitute is isomalt.

4. The composition of claim 1, wherein the polymer is selected from one or more of Polyvinylpyrrolidone, copovidone, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, hydroxypropylmethylcellulose acetate succinate, polyethylene oxides, poloxamers, polyacrylamides; polyvinyl acetate, polyvinyl alcohol, graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, carrageenans, galactomannans and xanthan gum or combinations thereof.

5. The composition of claim 4, wherein the polymer is hydroxypropyl cellulose.

6. The composition of claim 1, wherein said composition exhibits a disintegration time of more than 20 minutes.

7. The composition of claim 1, wherein said composition exhibits a disintegration time of more than 15 minutes.

8. The composition of claim 1, wherein said composition comprising:
(i) 25-50% w/w xylitol;
(ii) 15-60% w/w sugar substitute;
(iii) 1-15% w/w polymer; and
(iv) 1-50% w/w one or more excipients; based on total weight of the composition.

9. The composition of claim 1, wherein said composition glycemic load is not more than 10.

10. The composition of claim 1, wherein said composition is administered to quench thirst in patients associated with chronic kidney diseases (CKD), End-Stage Renal Disease (ESRD) or oncology supportive care treatment.