FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
A Laxative Composition Containing Combination Of Lactulose And Dextrin And Process For
Preparing The Same
2. APPLICANT
NAME : Abbott India Limited
NATIONALITY : IN
ADDRESS : 3-4, Corporate Park, Sion-Trombay Road, Mumbai - 400 071, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
Complete
The following specification describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION:
The present invention relates to a composition comprising combination of lactulose and dextrin and one or more excipients. The present invention further relates to a stable laxative composition in the form of oral solution comprising combination of lactulose and wheat dextrin and one or more excipients.
BACKGROUND OF THE INVENTION:
Lactulose is a synthetic, non-digestible sugar used in the treatment of chronic constipation and hepatic encephalopathy, a complication of liver disease mainly work as osmotic laxative. The efficacy of lactulose in these conditions is based on its fermentation in the colon by certain bacteria and the increase of the biomass of these bacteria in the colon. The products of fermentation are mainly organic acids, such as lactic acid and small-chain fatty acids, which, by exerting a local osmotic effect in the colon, result in increased fecal bulk and stimulation of peristalsis.
Wheat dextrin is a natural water soluble fiber and it contains a 100% natural fiber used as bulk laxative for the treatment of constipation. Wheat dextrin is made of fibrins and mucilage. During increased water retention in the intestine fibrins swell to more than 7 times its size. Thus increasing the stool mass and provide shape to the stool. The mucilage is slimy substance which stimulates the intestinal walls, thereby inducing peristaltic movement.
Use of lactulose alone as osmotic laxative is well known in the art and also use of dextrin such as wheat dextrin as bulk laxative is also well known in the art. However lactulose alone is prone to produce lactulose induced diarrhea and wheat dextrin alone fails to provide complete defecation.
Thus there is need in the art for more effective laxative composition which could provide complete defecation with satisfaction of relieving without producing diarrhea. Thus present inventors have come up with a solution to these shortcomings by providing a laxative composition comprising combination of lactulose and dextrin and one or more excipients.

SUMMARY OF THE INVENTION:
The present invention relates to a composition comprising combination of lactulose and dextrin and one or more excipients.
The present invention further relates to a laxative composition comprising combination of lactulose and wheat dextrin and one or more excipients.
In one specific aspect, the present invention relates to a composition consisting essentially of a combination of lactulose and wheat dextrin, and one or more excipients.
The present invention further relates to a composition comprising combination of lactulose and wheat dextrin and one or more excipients wherein the composition is in the form of oral solution.
The present invention further relates to a laxative composition in the form of stable oral solution comprising combination of lactulose and wheat dextrin and one or more excipients.
The present invention further relates to a process of preparing a composition comprising combination of lactulose and wheat dextrin and one or more excipients.
In one specific aspect, the present invention relates to a process of preparing a laxative composition consisting essentially of combination of lactulose and wheat dextrin and one or more excipients.
The present invention further relates to a method of treating chronic constipation by administering a composition comprising combination of lactulose and dextrin and one or more excipients.
The present invention further relates to a method of treating hepatic encephalopathy by administering a composition comprising combination of lactulose and dextrin and one or more excipients.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a laxative composition, essentially intended for the treatment of chronic constipation and hepatic encephalopathy.
Laxative drugs are necessary in the cases, such as functional constipation or in special situations, such as hepatic encephalopathy. Constipation very frequently occurs and affects a large number of individuals with no distribution as regards sex or age. It’s causes and consequences vary considerably.
Lactulose was prepared in 1930, was proposed in about 1960, in solution form, for the treatment of constipation. Numerous toxicological, pharmacological and clinical studies showed its harmlessness and effectiveness. The product has been marketed in various countries in syrup form (Duphalac in France 1972).
Lactulose is industrially manufactured by the isomerization of lactose under the influence of various alkaline agents. No matter what the said agent, the lactulose obtained is accompanied by related sugars, the most important of these being galactose and lactose.
Lactulose when administered in humans acts as osmotic laxative however in some cases lactulose tend to induce diarrhea. Further, lactulose acts as osmotic laxative and in majority cases produce watery stool and fails to provide complete evacuation or relieving satisfaction to the chronic constipation patients.
The present inventors found that the problem associated with lactulose can be overcome by a laxative composition comprising combination of lactulose and dextrin wherein lactulose works as osmotic laxative and dextrin, preferably wheat dextrin, works as a bulk laxative.
Lactulose increases the water retention in the stool, thereby softening the stool. The mucilage in the wheat dextrin, stimulate the intestinal walls, inducing the peristaltic movement in the intestine and being slimy ensure smooth passage of the stool.

However, formulating a stable clear oral solution formulation/composition comprising both lactulose and wheat dextrin has been a challenge, which is evidenced by the absence of such a clear oral solution comprising lactulose and wheat dextrin. Some of the major problems to manufacture clear and stable formulations of lactulose and wheat dextrin are:
. Compatibility studies of Lactulose & Wheat Dextrin, since the combination is not available worldwide.
. Selection of dosage
. Feasibility trials
. Analysis & compliance of physio-chemical parameters of formulation
. Selection of preservative & preservative efficacy analysis
. Forced degradation studies
. Analytical method of development
The present inventors have now surprisingly found that compositions containing combination of lactulose and wheat dextrin can be obtained in a clear solution form which is stable and palatable. Lactulose is in liquid form and wheat dextrin is available in solid form. Hence, formulating a clear and stable solution using solid powder of wheat dextrin with lactulose is a challenge. However, the present invention provides a clear and stable solution comprising wheat dextrin and lactulose. The stability of the clear solution is obtained by maintaining the pH of the solution between 4 and 7. Also, preservatives such as sodium benzoate are added to the solution. Wheat dextrin is a fiber and it's compatibility with lactulose in the same formulation is not known. It is only in the present invention that a solution formulation has been developed comprising both wheat dextrin and lactulose, and yet the solution is clear and stable.
Further, the present inventors have also found that by combining lactulose and wheat dextrin, the required dose of lactulose could be substantially reduced. Currently, stimulant laxatives are primarily used prior to surgery, which induce severe diarrhea. The inventors of this application have found that a formulation of lactulose and wheat dextrin is a better product (when formulated appropriately) and hence, a patient would prefer to use the formulation of the present invention, as it would be more patient

compliant and will give good results. The combination of lactulose and wheat dextrin is therapeutically superior to plain lactulose. In case of Idiopathic Chronic Constipation, the patient besides having soft stool, also needs the stimulation (the peristaltic movement induced due to wheat dextrin). Also wheat dextrin being a bulk laxative makes sure that complete stool is emptied. The inventors of the present application find that while lactulose works brilliantly in case of mild to medium constipation, combination of lactulose and wheat dextrin would work in acute and chronic constipation. A combination product of lactulose with wheat dextrin is not available. Hence, a new formulation is needed for better therapeutic action, which contains both lactulose and wheat dextrin. The primary goal of the present invention was to formulate a stable acceptable oral solution containing lactulose and wheat dextrin formulation, and it was developed in such a way that, it could be easily manufactured and it is stable in amber colored PET and amber colored Glass bottles with ROPP cap.
Advantages of combination of lactulose and wheat dextrin:
. Facilitates production of soft, bulky, well-formed stools; and gentle, strain-free evacuation
. Increased production of saccharolytic bacteria; additive prebiotic effect (soluble > insoluble fiber)
. Bulk laxatives are more prophylactic than therapeutic (no action on preformed stools already present in the rectum); lactulose regulates physiological rhythm of the colon
. Fiber is associated with decrease in hyperlipemia and atherosclerosis. Lactulose has Hypolipidaemic action and is the laxative of choice in cardiac and diabetic patients with normal transit time, including metabolic syndrome.
. Synergistic action of combination - prevents ‘straining-at-stool’, and is recommended in constipation associated with hemorrhoids/anal fissures/post-operative constipation (soft stool).
. Bulk laxatives help to compensate lack of fiber in diet of children; lactulose endorsed as “laxative of choice in children”. Combination constitutes a synergistic combination as per treatment algorithm of constipation in children. Hence, combination can be recommended in the pediatric population also.

Further, present inventors have also found that the pH of the composition which is in the form of oral solution is critical for the stability and clarity of the final composition. The compositions were found to be stable and clear between pH 4 to pH 7. The preferred pH for the oral solution is between pH 5 and pH 7.
While developing the formulation of present invention present inventors found that a specified ratio of lactulose to wheat dextrin produces a clear solution and beyond this the crystals are formed. The compositions were found to be clear when the ratio of lactulose to dextrin is in the range of 1:0.5 to 4:1.5. In a preferred embodiment, the ratio of lactulose to dextrin is 2:0.7.
Accordingly, in one embodiment the present invention provides a composition comprising combination of lactulose and dextrin and one or more excipients.
Another embodiment of the present invention provides a laxative composition comprising combination of lactulose and dextrin and one or more excipients.
In yet another embodiment, present invention provides a laxative composition comprising combination of lactulose and wheat dextrin and one or more excipients.
In yet another embodiment, present invention provides a laxative composition comprising combination of lactulose and wheat dextrin and one or more excipients wherein the composition is in the form of oral solution.
In yet another embodiment, present invention provides a laxative composition comprising combination of lactulose and wheat dextrin and one or more excipients wherein the composition is in the form of oral solution wherein the pH of the composition is from 4 to 7. In a preferred embodiment, the pH of the composition is from 5 to 7.
In yet another embodiment, the present invention provides a composition in the form of stable oral solution comprising combination of lactulose and wheat dextrin and one or more excipients.

In a specific embodiment, present invention provides a laxative composition in the form of stable oral solution comprising combination of lactulose and wheat dextrin and one or more excipients.
In one embodiment, the present invention provides a method of preparing an oral solution composition comprising a combination of lactulose and a dextrin, and one or more excipients. The method comprises:
(a) dissolving dextrin and one or more excipients in purified water,
(b) adding lactulose with stirring in solution of step (a) until clear viscous solution is obtained, and
(c) adjusting the pH of the solution between 4 and 7.
In yet another embodiment present invention provides a process of preparing a laxative composition comprising combination of lactulose and wheat dextrin and one or more excipients wherein process has following steps:
(a) dissolving wheat dextrin and one or more excipients in purified water;
(b) adding lactulose concentrate with stirring in solution of step a) until clear viscous solution is obtained;
(c) adjusting the pH of the solution.
In yet another embodiment the present invention provides a laxative composition comprising:
(a) 50% w/v of lactulose concentrate,
(b) 17.5% w/v of wheat dextrin,
(c) 0.3% w/v of sodium benzoate,
(d) and one or more excipients.
In yet another embodiment present invention provides a method of treating chronic constipation by administering a composition comprising combination of lactulose and dextrin and one or more excipients.

In yet another embodiment present invention provides a method of treating hepatic encephalopathy by administering a composition comprising combination of lactulose and dextrin and one or more excipients.
The composition of the present invention may also contain other excipients, such as buffering agents, preservative, colors or flavours. The excipients that are useful in preparing composition are preferably safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for human use.
The buffering agents according to present invention can be selected from group consisting of potassium dihydrogen phosphate, disodium hydrogen phosphate dihydrate, glycine/sodium hydroxide, sodium carbonate/sodium hydrogen carbonate, sodium tetraborate/sodium hydroxide, sodium bicarbonate/sodium hydroxide and the like or combinations thereof.
The buffering agents are present from 0.05% w/v to 1.5% w/v of the composition.
The preservative according to present invention may be selected from the group consisting of sodium benzoate, sorbates, EDTA, domiphen bromide, butylparaben, propylparaben, ethylparaben, methylparaben, paraben salts and mixtures thereof and the like.
The preservatives are present in the amount of about 0.01% w/v to about 1.5% w/v of the composition.
Optional ingredients include a coloring agent to impart a pleasant color and flavoring agent to impart a pleasant flavor, thus improving the organoleptic properties of the solution. Color selection can be made consistent with flavor. Water is present as the major component as vehicle of the composition and to adjust desired volume of the composition.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the present invention. The examples should not be read as limiting the scope of the present invention.

Examples Example No. 1
Table No. 1

Ingredient Qty/liter
Lactulose concentrate USP (72%) 748 ml
Wheat dextrin 175 g
Propylene glycol 200 g
Purified water q.s.
Manufacturing Process:
1. Take 100 ml purified water and add propylene glycol,
2. With constant stirring mix wheat dextrin in solution obtained in step 1,
3. Add lactulose concentrate to solution obtained in step 2 with continuous stirring until the clear viscous solution is obtained,
4. Check and adjust the pH of the solution obtained in step 3 between 4.0 and 6.0, and make up the volume with purified water.
Example No. 2
Table No. 2

Ingredient Qty/liter
Lactulose concentrate USP (72%) 748 ml
Wheat dextrin 175 g
Sodium methyl paraben 2 g
Sodium propyl paraben 200 mg
Purified water q.s.
Manufacturing Process:
1. Take 100 ml purified water and add and dissolve sodium methyl paraben, sodium propyl paraben,

2. With constant stirring mix wheat dextrin in solution obtained in step 1,
3. Add lactulose concentrate to solution of step 2 with continuous stirring until the clear viscous solution is obtained,
4. Check and adjust the pH of the solution of step 3 between 4.0 and 6.0, and make up the volume with purified water.
Example No. 3
Table No. 3

Ingredient Qty/liter
Lactulose concentrate USP (72%) 748 ml
Wheat dextrin 175 g
Sodium benzoate 3 g
Purified water q.s.
Manufacturing Process:
1. Dissolve sodium benzoate in water at 500C and cool it,
2. With constant stirring mix wheat dextrin in solution obtained in step 1,
3. Add lactulose concentrate to solution of step 2 with continuous stirring until the clear viscous solution is obtained,
4. Check and adjust the pH of the solution of step 3 between 5.0 and 7.0, and make up the volume with purified water.
Example No. 4
Table No. 4

Ingredient Qty/50liter
Lactulose concentrate USP (72%) 33.33 liter
Wheat dextrin 10.44 kg
Sodium benzoate 0.15 kg
Purified water q.s.
Manufacturing Process:

1. Charge 5 liter preheated (70-800C) purified water in clean stainless steel vessel and add sodium benzoate with continuous stirring for 15 minutes at 15 rpm,
2. Add wheat dextrin in solution obtained in step 1 with continuous mixing for 10 minutes at 15 rpm and keep for soaking for 2 hours,
3. Add lactulose concentrate to the solution obtained in step 2 with continuous stirring for 25 minutes at 15 rpm,
4. Check and adjust the pH of the solution between 5.0 and 7.0,
5. Make up the volume up to 50 liters of solution obtained in step 3 and check the pH of the final solution.
Drug-Excipient Compatibility Study:
A compatibility study using the core excipients of the selected formulation was
performed as shown in Table No. 5.
Table No. 5

Sample ID Drug substance Drug substance /Excipient API Excipient Ratio Conditions Time
1 Lactulose concentrate Sodium benzoate 1:1 40ºC + 2ºC / 75% RH + 5% RH 90 days
2 Lactulose concentrate Wheat Dextrin 1:1

3 Wheat Dextrin Sodium benzoate 1:1

Note: For mixed for each mixture, the in approximately 1 m gredients were accur inute ately weighted in to a suitable glass bottl e and
The results of the drug excipients compatibility study are presented in Table No. 6
Table No. 6
Sample ID Sample description Impurities (%)

Initial |40ºC/75% RH; 90 days

Physical description Highest
unknown
impurity Total impurities Physical description Highest
unknown
impurity Total impurities
1 Lactulose concentrate and Sodium Benzoate Yellowish colored clear solution NA* NA* Yellowish colored clear solution NA* NA*

2
Lactulose concentrate and Wheat Dextrin Yellowish colored clear solution NA* NA* Yellowish colored clear solution NA* NA*
3 Wheat Dextrin and Sodium Benzoate White to off white colored powder NA* NA* White to off white colored powder NA* NA*
The mixture of drug and excipient did not show any increase in impurities level, when stored at 40ºC/75% RH up to 90 days. The above observations showed that there is no drug-excipient interaction at 40ºC + 2ºC / 75% RH + 5% RH. Accelerated and long term stability data of feasibility trial batches confirmed compatibility of drug substance with excipients.

Three batches of composition as shown in table No. 4 was manufactured and packed in amber colored 100 ml PET bottles and amber colored 100 ml glass bottles and subjected to stability studies at different stability conditions and obtained results are presented below in table No. 7.
Table No. 7

Tests Batch Initial Conditions / Duration

Accelerated (40°C±2°C,75%RH±5%RH) Real Time
(30°C ±2°C, 65% RH ±
5%RH)

1M 2M 3M 3M

Amb PET Amb Glass Amb PET Amb Glass Amb PET Amb Glass Amb PET Amb Glass
pH A 6.02 5.57 5.61 5.6 5.7 5.91 5.96 5.79 6.01

B 6.02 5.59 5.63 5.6 5.65 5.86 5.84 5.87 5.81

C 6.02 5.66 5.67 5.61 5.56 5.85 5.88 5.85 5.72
Assay (%)
Lactulose A 103.2 102.4 102.4 103.92 102.4 100 100.8 102.4 101.6

B 105.2 104.8 105.6 102.8 102.4 99.2 100.4 100 101.6

C 104.0 104.8 101.6 102.3 100.4 100.8 99.2 101.6 100.8
Wheat dextrin A 105.83 104 104.69 105.8 106.4 103.2 104.34 104.1 103.9

B 102.63 100.34 102.4 101.9 104.46 100.1 101.6 100.46 103.9

C 105.3 105.26 102.5 106.17 104.2 102.74 101.94 103.43 102.97
Sodium benzoate A 100 99.33 98.33 99.86 98.83 100.7 101.13 100.86 99.2

B 97.27 97.13 97.66 98.4 98.8 98.13 98.53 97.53 99.2

C 100.27 99.8 98.73 100.06 99.0 99.53 98.93 100.3 99.67
M: Month
Amb PET: Amber colored 100 ml PET bottle Amb Glass: Amber colored 100 ml Glass bottle Above stability results showed that no significant degradation was observed in both lactulose and wheat dextrin. This indicates that the
compositions were stable over the period of time. Also the pH of the composition was found to be critical for the stability of the composition.
Three more batches of composition as shown in table No. 4 were manufactured and packed in amber colored 100 ml PET bottles and amber colored 100 ml glass bottles and subjected to stability studies at different stability conditions and the 12 months real time stability study data obtained are presented below in table Nos. 8 to 13.

Table No. 8

STABI LITY SUMMARY S HEET(Real Time) lution
bottle Batch Size : 50 Litre eq. Lactulose –2.5 g Wheat Dextrin –0.875 g Sodium Benzoate IP --
Product Name : Lactulose & Wheat Dextrin Oral So Storage Condition : 30±2ºC, 6.5±5% RH
Packing : 100 ml packed in amber colored PET Label claim: Each 5 ml. contains : Lactulose Concentrate USP 15 mg Aqueous Base --qs

S. No. Parameter Specification Initial 3 Month 6 Month 9 Month 12 Month
1 Description Yellowish colored clear viscious solution Yellowish
colored
clear
viscious
solution Yellowish
colored
clear
viscious
solution Yellowish colored clear viscious solution Yellowish
colored
clear
viscious
solution Yellowish
colored
clear
viscious
solution
2 Identification Lactulose, Wheat Dextrin and Sodium Benzoate The retention time of the major peak of Lactulose, Wheat Dextrin and Sodium Benzoate in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation, as obtained in the assay Complies Complies Complies Complies Complies
3 pH 5.0 to 7.0 ( 15 minutes after contact with Electrode) 6.02 5.87 5.88 5.85 5.82

4 Refractive Index Not less than 1.45 at 20ºC 1.455 1.457 1.454 1.456 1.455
5 Related Compound
a) Fructose
b) Galactose
c) Epilactose
d) Lactose a) Not more than 1.00%
b) Not more than 16.00%
c) Not more than 8.00%
d) Not more than 12.00% a) 0.003%
b) 5.77%
c) 0.71%
d) 3.69% a) 0.0059%
b) 6.55%
c) 0.88%
d) 4.02% a) 0.0071%
b) 6.79%
c) 0.95%
d) 4.23% a) 0.0078%
b) 6.86%
c) 0.99%
d) 4.49% a) 0.0095%
b) 7.17%
c) 1.19%
d) 4.95%
6 Microbial Test a) Total Bacterial Count-b) Total Fungal Count (Total Yeast and Mould Count) c) Pathogens
1) E. Coli
2) Salmonella sp. a) NMT 100cfu/g
b) NMT 10cfu/g
c)
1) Should be absent/g
2) Should be absent/g a) 55cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 35cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 30cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 35cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 35cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent
7 Assay

Lactulose NLT 95% TO NMT 110% 105.20% 100% 102% 101.60% 100.40%

NLT 2.38g - NMT 2.75g 2.63g 2.5g 2.55g 2.54g 2.51g

Wheat Dextrin NLT 95% TO NMT 110% 102.63% 100.46% 101.60% 99.54% 98.99%

NLT 0.83g - NMT 0.96g 0.898g 0.879g 0.889g 0.871g 0.866g

Sodium Benzoate NLT 95% TO NMT 110% 97.27% 97.53% 97.40% 97.33% 97.67

NLT 14.25 mg - NMT 16.5 mg 14.59mg 14.63mg 14.61mg 14.6mg 14.65mg

Table No. 9

STABILITY SUMMARY SHEET(Real Time)
Product Name : Lactulose & Wheat Dextrin Oral Solution Storage Condition : 30±2ºC, 6.5±5% RH
Packing : 100 ml packed in amber colored PET bottle Batch Size : 50 Litre
Label claim: Each 5 ml. contains : Lactulose Concentrate USP eq. Lactulose -2.5 g Wheat Dextrin -0.875 g Sodium Benzoate IP --15 mg
Aqueous Base --qs
S. No. Parameter Specification Initial 3 Month 6 Month 9 Month 12 Month
1 Description Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution
2 Identification Lactulose, Wheat Dextrin & Sodium Benzoate The retention time of the major peak of Lactulose, Wheat Dextrin & Sodium Benzoate in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation, as obtained in the assay Complies Complies Complies Complies Complies
3 pH 5.0 to 7.0 (15 minutes after contact with electrode) 6.02 5.79 5.81 5.8 5.84
4 Refractive index Not less than 1.451 at 20ºC 1.458 1.456 1.455 1.457 1.456

5 Related Compund
a) Fructose
b) Galactose
c) Epilactose
d) Lactose a) Not more than 1.00%
b) Not more thatn16.00%
c) Not more than 8.00 %
d) Not more than 12.00% a) 0.0002%
b) 5.75%
c) 0.63%
d) 6.26% a) 0.0072%
b) 6.59%
c) 0.86%
d) 4.04% a) 0.0086%
b) 6.65%
c) 0.87%
d) 4.07% a) 0.0097%
b) 6.77%
c) 0.94%
d) 4.40% a) 0.0116%
b) 7.27%
c) 1.19%
d) 5.04%
6 Microbial Test

a) Total Bacterial Count-b) Total Fungal Count (Total Yeast and Mould Count)
c) Pathogens
1) E. Coli
2) Salmonella sp. a) NMT 100cfu/g
b) NMT 10cfu/g
c)
1) Should be absent/g
2) Should be absent/g a) 30cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 20cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 25cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 25cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 25cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent
7 Assay

Lactulose NLT 95% TO NMT 110% 103.20% 102.40% 100% 99.6% 99.2%

NLT 2.38g - NMT 2.75g 2.58g 2.56g 2.5g 2.49g 2.48g

Wheat Dextrin NLT 95% TO NMT 110% 105.83% 104.1% 102.5% 101.03% 98.86%

NLT 0.83g - NMT 0.96g 0.926g 0.911g 0.897g 0.884g 0.865g

Sodium Benzoate NLT 95% TO NMT 110% 100.00% 100.86% 101% 100.20% 98.20%

NLT 14.25 mg - NMT 16.5 mg 15.0mg 15.13mg 15.15mg 15.03mg 14.73mg

Table No. 10

STABILITY SUM MARY SHEE T(Real Time) trin –0.875 g S : 50 Litre odium Benzoat
Product Name : Lactulose & Wheat Dextrin Oral Solution Storage Condition : 30±2ºC, 6.5±5% RH
Packing : 100 ml packed in amber colored PET bottle Batch Size Label claim: Each 5 ml. contains : Lactulose Concentrate USP eq. Lactulose -2.5 g Wheat Dex Aqueous Base --qs

e IP --15 mg
S. No. Parameter Specification Initial 3 Month 6 Month 9 Month 12 Month
1 Description Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution
2 Identification Lactulose, Wheat Dextrin & Sodium Benzoate The retention time of the major peak of Lactulose, Wheat Dextrin & Sodium Benzoate in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation, as obtained in the assay Complies Complies Complies Complies Complies
3 pH 5.0 to 7.0 (15 minutes after contact with electrode) 6.02 5.85 5.8 5.78 5.83
4 Refractive index Not less than 1.451 at 20ºC 1.452 1.455 1.455 1.453 1.457

5 Related Compund
a) Fructose a) Not more than 1.00% a) 0.00068% a) 0.0059% a) 0.0069% a) 0.0081% a) 0.0104%
b) Galactose b) Not more thatn 16.00% b) 6.07% b) 6.11% b) 6.85% b) 6.93% b) 7.16%
c) Epilactose c) Not more than 8.00 % c) 0.595% c) 0.86% c) 0.92% c) 0.97% c) 1.18%
d) Lactose d) Not more than 12.00% d) 3.27% d) 3.97% d) 4.27% d) 4.56% d) 5.07%
6 Microbial Test
a) Total Bacterial Count-b) Total Fungal a) NMT 100cfu/g a) 20cfu/g a) 15cfu/g a) 25cfu/g a) 20cfu/g a) 20cfu/g

b) NMT 10cfu/g b) <10cfu/g b) <10cfu/g b) <10cfu/g b) <10cfu/g b) <10cfu/g
Count (Total Yeast and Mould Count)
c) Pathogens c) c) c) c) c) c)
1) E. Coli 1) Should be absent/g 1) Absent 1) Absent 1) Absent 1) Absent 1) Absent
2) Salmonella sp. 2) Should be absent/g 2) Absent 2) Absent 2) Absent 2) Absent 2) Absent
7 Assay

Lactulose NLT 95% TO NMT 110% 104.00% 101.60% 100.80% 100.40% 100.00%

NLT 2.38g - NMT 2.75g 2.6g 2.54g 2.52g 2.51g 2.50g

Wheat Dextrin NLT 95% TO NMT 110% 105.03% 103.43% 102.4% 101.70% 99.09%

NLT 0.83g - NMT 0.96g 0.919g 0.905g 0.896g 0.890g 0.867g

Sodium Benzoate NLT 95% TO NMT 110% 100.27% 100.30% 98.53% 98.20% 97.40%

NLT 14.25 mg - NMT 16.5 mg 15.04 mg 15.05 mg 14.78 mg 14.73 mg 14.61 mg

Table No. 11

STABILITY SUMMARY SHEE T(Real Time) –0.875 g Sodi : 50 Litre um Benzoate I P --15 mg
Product Name : Lactulose & Wheat Dextrin Oral Solution Storage Condition : 30±2ºC, 6.5±5% RH
Packing : 100 ml packed in amber colored glass bottle Batch Size
Label claim: Each 5 ml. contains : Lactulose Concentrate USP eq. Lactulose -2.5 g Wheat Dextrin
Aqueous Base --qs

S. No. Parameter Specification Intial 3 Month 6 Month 9 Month 12 Month
1 Description Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution
2 Identification Lactulose, Wheat Dextrin & Sodium Benzoate The retention time of the major peak of Lactulose, Wheat Dextrin & Sodium Benzoate in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation, as obtained in the assay Complies Complies Complies Complies Complies
3 pH 5.0 to 7.0 (15 minutes after contact with electrode) 6.01 5.81 5.76 5.75 5.72
4 Refractive index Not less than 1.451 at 20ºC 1.454 1.453 1.455 1.456 1.455
5 Related Compund
a) Fructose
b) Galactose
c) Epilactose
d) Lactose a) Not more than 1.00%
b) Not more thatn 16.00%
c) Not more than 8.00 %
d) Not more than 12.00% a) 0.0007%
b) 6.21%
c) 0.76%
d) 3.3% a) 0.0052%
b) 6.51%
c) 0.72%
d) 4.12% a) 0.0058%
b) 6.54%
c) 0.94%
d) 4.38% a) 0.0069%
b) 6.59%
c) 1.02%
d) 4.65% a) 0.0092%
b) 7.00%
c) 1.22%
d) 5.18%

6 Microbial Test
a) Total Bacterial Count-b) Total Fungal Count (Total Yeast and Mould Count)
c) Pathogens
1) E. Coli
2) Salmonella sp. a) NMT 100cfu/g
b) NMT 10cfu/g
c)
1) Should be absent/g
2) Should be absent/g a) 50 cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 25cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 30cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 35cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 30 cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent
7 Assay

Lactulose NLT 95% TO NMT 110% 104.80% 101.60% 102.00% 101.20% 100.00%

NLT 2.38g - NMT 2.75g 2.62g 2.54g 2.55g 2.53g 2.50g

Wheat Dextrin NLT 95% TO NMT 110% 101.83% 103.9% 100% 99.09% 98.29%

NLT 0.83g - NMT 0.96g 0.891g 0.909g 0.875g 0.867g 0.860g

Sodium Benzoate NLT 95% TO NMT 110% 97.87% 99.20% 98.87% 98.07% 97.73%

NLT 14.25 mg - NMT 16.5 mg 14.68mg 14.88mg 14.83mg 14.71mg 14.66mg

Table No. 12

STABILITY SUMMARY SHEET Real Time) –0.875 g Sodi : 50 Litre um Benzoate I P --15 mg
Product Name : Lactulose & Wheat Dextrin Oral Solution Storage Condition : 30±2ºC, 6.5±5% RH
Packing : 100 ml packed in amber colored glass bottle Batch Size
Label claim: Each 5 ml. contains : Lactulose Concentrate USP eq. Lactulose -2.5 g Wheat Dextrin
Aqueous Base -qs

S. No. Parameter Specification Intial 3 Month 6 Month 9 Month 12 Month
1 Description Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution
2 Identification Lactulose, Wheat Dextrin & Sodium Benzoate The retention time of the major peak of Lactulose, Wheat Dextrin & Sodium Benzoate in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation, as obtained in the assay Complies Complies Complies Complies Complies
3 pH 5.0 to 7.0 (15 minutes after contact with electrode) 6.04 5.92 5.86 5.84 5.83
4 Refractive index Not less than 1.451 at 20ºC 1.455 1.456 1.454 1.453 1.456
5 Related Compund
a) Fructose
b) Galactose
c) Epilactose
d) Lactose a) Not more than 1.00%
b) Not more thatn 16.00%
c) Not more than 8.00 %
d) Not more than 12.00% a) 0.0007%
b) 5.79%
c) 0.65%
d) 3.4% a) 0.0047%
b) 6.60%
c) 0.83%
d) 3.96% a) 0.0071%
b) 6.64%
c) 0.96%
d) 4.10% a) 0.0075%
b) 6.74%
c) 0.99%
d) 4.39% a) 0.0092%
b) 7.16%
c) 1.25%
d) 4.98%

6
Microbial Test

a) Total Bacterial Count- a) NMT 100cfu/g
b) NMT 10cfu/g
c)
1) Should be absent/g
2) Should be absent/g a) 40 cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 25cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 30cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 30cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 25 cfu/g

b) Total Fungal Count (Total Yeast and Mould Count)




b) <10cfu/g

c) Pathogens




c)

1) E. Coli




1) Absent

2) Salmonella sp.




2) Absent
7 Assay

Lactulose NLT 95% TO NMT 110% 103.60% 101.6% 98.4% 98% 100.8%

NLT 2.38g - NMT 2.75g 2.54g 2.54g 2.46g 2.45g 2.52g

Wheat Dextrin NLT 95% TO NMT 110% NLT 0.83 g - NMT 0.96 g 104.0% 0.910 g 105.49% 0.923 g 103.2% 0.903 g 99.54% 0.871 g 98.17% 0.859 g

Sodium Benzoate NLT 95% TO NMT 110% 98.53% 101.67% 100.53% 99.93% 97.87%

NLT 14.25 mg - NMT 16.5 mg 14.78mg 15.25mg 15.08mg 14.99mg 14.68mg

Table No. 13

STABILITY SUMMARY SHE ET(Real Time) –0.875 g Sodi : 50 Litre um Benzoate I P --15 mg
Product Name : Lactulose & Wheat Dextrin Oral Solution Storage Condition : 30±2ºC, 6.5±5% RH
Packing : 100 ml packed in amber colored glass bottle Batch Size
Label claim: Each 5 ml. contains : Lactulose Concentrate USP eq. Lactulose -2.5 g Wheat Dextrin
Aqueous Base -qs

S. No. Parameter Specification Intial 3 Month 6 Month 9 Month 12 Month
1 Description Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution Yellowish colored clear viscous solution
2 Identification Lactulose, Wheat Dextrin & Sodium Benzoate The retention time of the major peak of Lactulose, Wheat Dextrin & Sodium Benzoate in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation, as obtained in the assay Complies Complies Complies Complies Complies
3 pH 5.0 to 7.0 (15 minutes after contact with electrode) 6.05 5.72 5.89 5.85 5.87
4 Refractive index Not less than 1.451 at 20ºC 1.4547 1.455 1.453 1.456 1.454
5 Related Compound
a) Fructose
b) Galactose
c) Epilactose
d) Lactose a) Not more than 1.00%
b) Not more thatn 16.00%
c) Not more than 8.00 %
d) Not more than 12.00% a) 0.0014%
b) 5.93%
c) 0.62%
d) 3.37% a) 0.0059%
b) 6.41%
c) 0.89%
d) 3.99% a) 0.0067%
b) 6.62%
c) 0.94%
d) 4.02% a) 0.0078%
b) 6.70%
c) 0.96%
d) 4.26% a) 0.0092%
b) 7.08%
c) 1.19%
d) 4.90%

6
Microbial Test
a) Total Bacterial Count-b) Total Fungal Count (Total Yeast and Mould Count)
c) Pathogens
1) E. Coli
2) Salmonella sp. a) NMT 100cfu/g
b) NMT 10cfu/g
c)
1) Should be absent/g
2) Should be absent/g a) 15 cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 10cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 20cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 15cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent a) 20 cfu/g
b) <10cfu/g
c)
1) Absent
2) Absent
7 Assay

Lactulose NLT 95% TO NMT 110% 103.2% 100.8% 101.2% 100.8% 100.4%

NLT 2.38g - NMT 2.75g 2.58g 2.52g 2.53g 2.52g 2.51g

Wheat Dextrin NLT 95% TO NMT 110% 103.89% 102.97% 103.1% 99.89% 98.97%

NLT 0.83g - NMT 0.96g 0.909g 0.901g 0.902g 0.874g 0.866g

Sodium Benzoate NLT 95% TO NMT 110% 98.87% 99.67% 99.4% 99.33% 98.6%

NLT 14.25 mg - NMT 16.5 mg 14.83mg 14.95mg 14.91mg 14.9mg 14.79mg

We Claim
1. An oral solution composition comprising a combination of lactulose and a dextrin, and one or more excipients.
2. The composition according to claim 1, wherein dextrin is wheat dextrin.
3. The composition according to any of the preceding claims, wherein the ratio of lactulose to dextrin is in the range of 1:0.5 to 4:1.5.
4. The composition according to any of the preceding claims, wherein the ratio of lactulose to dextrin is 2:0.7.
5. The composition according to any of the preceding claims, wherein the oral solution has a pH between 4 and 7.
6. The composition according to any of the preceding claims, wherein the oral solution has a pH between 5 and 7.
7. The composition according to any of the preceding claims, wherein the one or more excipients are selected from buffering agents, preservatives, colors and flavours.
8. The composition according to any of the preceding claims, wherein the buffering agent is selected from the group consisting of potassium dihydrogen phosphate, disodium hydrogen phosphate dihydrate, glycine/sodium hydroxide, sodium carbonate/sodium hydrogen carbonate, sodium tetraborate/sodium hydroxide, sodium bicarbonate/sodium hydroxide and combinations thereof.
9. The composition according to any of the preceding claims, wherein the buffering agent is present in an amount of 0.05% w/v to 1.5% w/v of the composition.
10. The composition according to any of the preceding claims, wherein the preservative is selected from the group consisting of sodium benzoate, sorbates, EDTA, domiphen bromide, butylparaben, propylparaben, ethylparaben, methylparaben, paraben salts and mixtures thereof.
11. The composition according to any of the preceding claims, wherein the preservative is present in an amount of about 0.01% w/v to about 1.5% w/v of the composition.
12. The composition according to any of the preceding claims, comprising water as the vehicle for the oral solution.
13. A composition comprising:

(a) 50% w/v of lactulose concentrate,
(b) 17.5% w/v of wheat dextrin,
(c) 0.3% w/v of sodium benzoate, and
(d) one or more excipients.
14. A method of preparing an oral solution composition comprising a
combination of lactulose and a dextrin, and pharmaceutically acceptable excipients,
the method comprising:
(a) dissolving dextrin and one or more excipients in purified water,
(b) adding lactulose with stirring in solution of step (a) until clear viscous solution is obtained, and
(c) adjusting the pH of the solution between 4 and 7.

15. The method according to claim 14, wherein the dextrin is wheat dextrin.
16. The method according to any of the preceding claims 14 and 15, wherein the lactulose is a lactulose concentrate.
17. The method according to any of the preceding claims 14 to 16, wherein the one or more excipients are selected from buffering agents, preservatives, colors and flavours.
18. The method according to any of the preceding claims 14 to 17, wherein the pH is adjusted using a buffering agent selected from the group consisting of potassium dihydrogen phosphate, disodium hydrogen phosphate dihydrate, glycine/sodium hydroxide, sodium carbonate/sodium hydrogen carbonate, sodium tetraborate/sodium hydroxide, sodium bicarbonate/sodium hydroxide and combinations thereof.