FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A NOVEL LIQUID RECTAL SPRAY DOSAGE FORM COMPRISING
BISCODYL"
2. APPLICANT:
(a) NAME: Lincoln Pharmaceuticals Limited
(b) NATIONALITY: Indian Company incorporated under the Companies
Act, 1956
(c) ADDRESS: Lincoln House, Science City Road, Sola,
Ahmedabad-380 060, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to a high concentrated liquid rectal spray dosage form comprising Bisacodyl and its pharmaceutically active salts, in unique blend of solvents along with mucoadhesive polymers, useful for the treatment of constipation and bowel evacuation before investigational procedures or surgery. The present invention also relates to a process for preparation thereof.
BACKGROUND OF THE INVENTION:
Bisacodyl (INN) is a stimulant laxative drug. It is typically prescribed for relief of constipation and for the management of neurogenic bowel dysfunction as well as part of bowel preparation before medical examinations, such as for a colonoscopy. Bisacodyl is a diphenylmethane (in fact, a modified triphenylmethane) derivative and was first used as a laxative in 1953 due to Its similarity to phenolphthalein.
Chemically, Bisacodyl is (pyridin-2-ylmethanediyl) dibenzene-4,l-diyl diacetate OR 4,4'-(pyridin-2-ylmethylene)bis(4,1 -phenylene) diacetate having structural formula as follows:

Bisacodyl was first patented in US Patent No. 2764590 as laxatives'and disinfectant.
US4403982 discloses a method of cleansing a person's entire colon of solid and/or liquid materials therein, comprising steps of: in the absence of any prior colon cleansing treatment by means of orally taken laxatives, filling the colon completely with an aqueous liquid by introducing the liquid through the anal opening in sufficient quantity to fill the colon to the extent of distending the wall of the colon from the rectum to the cecum, wherein the liquid includes an ingredient which assists the liquid in loosening and removing the solid material, assuring that the aqueous liquid is retained in the person's colon for a predetermined period of time, while said liquid is being retained in the colon,

causing motion of the liquid back and forth through the person's colon, such that the liquid moves relative to the walls of the colon to facilitate removal of solid materials from the colon lining, and removing all obstructions to permit the person to expel substantially the entire quantity of solids and liquids from the colon. The liquid contains wetting agent such as castile soap and laxative such as Bisacodyl.
US5525355 discloses a method for the manufacture of a laxative composition in unit dosage form which comprises the steps of melting a normally solid stool softener; dispersing and/or dissolving a stimulant laxative compound in the molten stool softener and mixing to obtain a uniform mixture; filling the molten dispersion into hard gelatin capsule shells; and allowing the capsules to cool and the melt or dispersion to solidify.
US7335664 discloses a composition and method for cleansing a colon prior to endoscopic procedure, particularly, a combination of bisacodyl, metoclopramide, sodium, and/or a phosphorus containing composition administered in sequential doses for preparing a colon prior to colonoscopy.
US7291324 discloses an oral stimulant laxative, such as bisacodyl, followed, after a biologically determined interval, by a reduced volume of a PEG in water solution cleanses the bowels and colon in preparation for diagnostic colonoscopy, without the profuse uncontrollable diarrhea that typically follows either ingestion of large volume isotonic ravages, or smaller volume hypertonic lavages.
US5843479 discloses a pharmaceutical composition in a unit dosage form for peroral administration in a human or lower animal, having a gastrointestinal tract comprising a small intestine and a colon with a lumen there through having an inlet to the colon from the small intestine, comprising: a. a safe and effective amount of rapidly dissolving bisacodyl incorporated into a compressed, bi-convex tablet, with a maximum diameter of about 4 mm to about 10 mm; b. a non-pH dependent smoothing coat applied to the tablet to provide a smooth tablet surface free from edges and sharp curves; and c. an enteric polymer coating material comprising at least one inner coating layer and only one outer coating layer; wherein the rapidly dissolving bisacodyl is released at a point near the inlet to, or within the colon; each of the inner coating layer(s) is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 5 to about 6.3; and the outer

coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 6,8 to about 7.2
US5670158 discloses pharmaceutical compositions in dosage unit form, for peroral administration of bisacodyl to a human or lower animal having a gastrointestinal tract, with a lumen there through, with a small intestine and a colon with a junction there between, comprising: (a) a safe and effective amount of rapidly-dissolving bisacodyl means; and (b) a delivery means which prevents the release of bisacodyl from the dosage form into the lumen of the gastrointestinal tract during transport of the dosage form through the lumen until the dosage form is near the junction between the small intestine and the colon or in the colon, and which then releases the bisacodyl in the lumen near the junction between the small intestine and the colon or within the colon., The invention also involves methods for providing laxation for humans and lower animals in need thereof by peroral administration of such compositions.
US5656290 discloses a pharmaceutical composition in a unit dosage form for peroral administration in a human or lower animal, having a gastrointestinal tract comprising a small intestine and a colon with a lumen there through having an inlet to the colon from the small intestine, comprising: a. a safe and effective amount of rapidly dissolving bisacodyl incorporated into or coated on the surface of a dosage form selected from the group consisting of a spherical substrate, an elliptical substrate, a hard capsule, or a compressed tablet, with a maximum diameter of about 3 mm to about 10 mm; and b. an enteric polymer coating material comprising at least one inner coating layer and one outer coating layer; wherein the dosage form has a smooth surface free from edges or sharp curves; the elliptical substrate and the hard capsule have a ratio of the long to short diameters of no greater than about 1.5; the rapidly dissolving bisacodyl is released at a point near the inlet to, or within the colon; each of the inner coating layer(s) is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 5 to about 6.3; and the outer coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 6.8 to about 7.2.
US5651983 relates to a pharmaceutical composition in a unit dosage form for peroral administration in a human or lower animal, having a gastrointestinal tract comprising a

small intestine and a colon with a lumen there through having an inlet to the colon from the small intestine, comprising: a. a safe and effective amount of rapidly dissolving bisacodyl incorporated into or coated on the surface of a dosage form selected from the group consisting of a spherical substrate, an elliptical substrate, a hard capsule, or a compressed tablet, with a maximum diameter of about 3 mm to about 10 mm; and b. an enteric polymer coating material; wherein the dosage form has a smooth surface free from edges or sharp curves; the elliptical substrate and the hard capsule have a ratio of the long to short diameters of no greater than about 1.5; the rapidly dissolving bisacodyl is released at a point near the inlet to, or within the colon; the enteric polymer coating material begins to dissolve in an aqueous media at a pH between about 5 to about 6.3; and the enteric polymer coating material has a coating thickness of at least about 250 mu.m.
W. Roth, K. Beschke, "Pharmacokinetics and Laxative Effect of Bisacodyl after Administration of Various Dosage Forms", (Arzneim.-ForschVDrug Res., Vol. 38(1), No. 4 (1988), pp. 570-574) discloses release of bisacodyl in the colon is a preferred mode of delivery of the drug in order to minimize systemic absorption of bisacodyl.
Contact of desacetyl bisacodyl with the mucosa of the colon stimulates sensory nerve endings to produce increased propulsive peristaltic contractions of the colon which accelerate movement of contents through the colon. Both bisacodyl and desacetyl bisacodyl are poorly water soluble with absorption reported from both the small intestine and the colon. Absorption from the small intestine may be greater than from the colon.
Bisacodyl is sold under the trade names Dulcolax/Durolax, Fleet, Alophen, Correctol, and Carter's Little Pills (formerly Carter's Little Liver Pills) as well as generically. It is usually sold as 5 mg tablets, 10 mg suppositories, or 5 mg pediatric suppositories. It is also available as a 1.25 fluid ounce prepackaged enema containing a 10 mg delivered dose of liquid bisacodyl.
Various dosage forms of bisacodyl such as tablet capsule and solution are commercially available; however, these dosage forms have certain side effects such as diarrhea or repeated bowel movements.

In view of the above state of art, the present inventors have come up with a composition in a high concentrated liquid rectal spray dosage form comprising therapeutically effective amount of Bisacodyl and its pharmaceutically active salts, is present in an amount of their pharmacologically active amount in unique blend of solvents along with mucoadhesive polymers, to provide relatively better effect than other dosage forms like rectal suppositories or tablets as it is in solution form. Further, the novel mode of delivery is useful for the treatment of constipation and bowel evacuation before investigational procedures or surgery.
SUMMARY OF THE INVENTION:
In accordance with the above, the present invention provides a high concentrated liquid rectal spray dosage form comprising therapeutically effective amount of Bisacodyl and pharmaceutically acceptable salts thereof in effective doses, especially for treatment of constipation and bowel evacuation before investigational procedures or surgery.
In a preferred aspect, the present invention provides a high concentrated liquid rectal spray composition comprising therapeutically effective amount of Bisacodyl and pharmaceutically acceptable salts, in unique blend of solvents along with mucoadhesive polymers and preservatives which gives a systemic effect of Bisacodyl via rectal route, for the treatment of constipation and bowel evacuation before investigational procedures or surgery.
The composition of the present invention afford a better patient compliance, better bioavailability, when compared to painful intramuscular injections and complicated application of rectal suppositories, as the present formulation is in solution form that can administered by spraying method.
In yet another aspect, the present invention provides a process for preparation of the said composition.

DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
In an embodiment, the present invention provides a high concentrated liquid rectal spray dosage form comprising therapeutically effective amount of Bisacodyl and pharmaceutically acceptable salts thereof; useful for the treatment of constipation and bowel evacuation before investigational procedures or surgery.
In a preferred embodiment, the present invention provides a high concentrated liquid rectal spray dosage form comprising therapeutically effective amount of high concentration of Bisacodyl and its pharmaceutically acceptable salts in a unique blend of solvents along with mucoadhesive polymers and preservatives which gives a systemic effect; useful for the treatment of constipation and bowel evacuation before investigational procedures or surgery.
A high concentration of Bisacodyl and its pharmaceutically acceptable salts are present in an amount of 2% to 10% w/v.
The unique blend of solvents as referred herein are selected from the group of triacetine, glycofurol, polyethylene glycol, propylene glycol, ethyl alcohol, cremophore ELP, solutol, transcutol, labrasol, capmul, captex, Benzyl alcohol, benzyl benzoate, ethyl oleate. The said solvents are present in an amount of 5% to 80% w/v.
Suitable mucoadhesive polymers are selected from group of polyvinyl pyrollidone K 30, Hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose. The said mucoadhesive polymers are present in an amount of 1% to 10% w/v.
Suitable pharmaceutically acceptable excipients are selected from group of preservatives, anti-oxidants, chelating agents, osmotic agents, permeation enhancers and the like.

Suitable preservatives are selected from the group of sodium methyl paraben, sodium propyl paraben, sodium benzoate, benzyl alcohol, ethyl alcohol, benzalkonium chloride and potassium sorbate. The said preservatives are present in an amount of 1 to 15% w/v.
Suitable antioxidants are selected from the group of Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate and thiourea; chelating agents such as disodium edentate; osmotic agents such as sodium chloride, mannitol, sorbitol, potassium chloride; and permeation enhancers such as transcutol, isopropyl myristate etc.
Bisacodyl is well absorbed via rectal route as compare to oral and transdermal route. Rectal cavity contains high vascularity for drug absorption. The present dosage form delivers micron size droplets to the large surface area of rectal cavity for excellent drug absorption. Further, it gives relatively uniform dose dispensing than other liquid formulation.
In another embodiment, the present invention provides a process for preparation of a high concentrated liquid rectal spray composition which comprises,
1) Weighing and mixing the solvents and preservatives in manufacturing vessel;
2) dissolving mucoadhesive polymers in solution of step 1 with continuous stirring; and
3) dissolving the active ingredient into step 1 with applying heat upto 50°C to 60°C.
In another preferred embodiment, the present invention provides a process for preparation of a high concentrated liquid rectal spray composition which comprises,
1) Weighing and mixing solvents such as Triacetine, Glycofurol and preservative such as Benzyl alcohol in manufacturing vessel;
2) dissolving mucoadhesive polymer, Polyvinylpyrollidone K30 in solution of step 1 with continuous stirring; and
3) dissolving active ingredient, Bisacodyl into step 1 by applying heat upto 50°C to 60°C.
In another embodiment, the invention provides a liquid rectal spray dispenser comprising therapeutically effective amount of high concentrated Bisacodyl and pharmaceutically acceptable salts in unique blend of solvents along with mucoadhesive polymers and preservatives. The composition is filled in a convenient container that can give the

formulation in form of fine droplets. Hence, it is easy to deliver even to the pediatrics. The formulation is palatable eventhough the drug concentration is relatively large.
The invention provides a composition which is in a high concentrated liquid rectal spray dosage form comprising therapeutically effective amount of Bisacodyl and pharmaceutically acceptable salts in unique blend of solvents along with mucoadhesive polymers and preservatives, wherein the said composition does not crystallize at very low temperature during storage.
The amount of Bisacodyl liquid rectal spray of the present invention is 0.2 ml per spray.
The following example, which includes preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. It will be appreciated by any person skilled in this art that the present invention includes following examples and further can be modified and altered within the technical scope of the present invention.
EXAMPLES:

Example 1
SR.NO INGREDIENTS Ranges [mg/spray (0.2 ml)]
1 Bisacodyl Active 2%to l0%w/v
2 Triacetine Solvent 5 % to 80% w/v
3 Glycofurol Solvent 5 % to 80% w/v
4 Polyvinylpyrollidone K30 Mucoadhesive polymers 1% to 10% w/v
5 Benzyl alcohol Preservative 1% to 15% w/v
Total 100% w/v

Example 2
SR.NO INGREDIENTS Amount
[mg/spray (0.2 ml)]
1 Bisacodyl Active ingredient 5% w/v
2 Triacetine Solvent 68% w/v
3 Glycofurol Solvent 20 % w/v
4 Polyvinylpyrollidone K30 Mucoadhesive polymers 5 % w/v
5 Benzyl alcohol Preservative 2% w/v
Total 100% w/v
Example 3:
SR.NO INGREDIENTS Amount [mg/spray (0.2 ml)]
1 Bisacodyl Active ingredient 2.5% w/v
2 Triacetine Solvent 65.5% w/v
3 Glycofurol Solvent 23% w/v
4 Polyvinylpyrollidone K30 Mucoadhesive polymers 4% w/v
5 Benzyl alcohol Preservative 5% w/v
Total 100% w/v
Example 4:
SR.NO INGREDIENTS Amount
[mg/spray (0.2 ml)]
1 Bisacodyl Active ingredient 2.5% w/v
2 Polyethylene glycol 400 Solvent 59 % w/v
3 Glycofurol Solvent 24.5% w/v
4 Polyvinylpyrollidone K 30 Mucoadhesive polymers 5 % w/v
5 Ethyl alcohol Preservative 5% w/v
Total 100% w/v

We Claim,
1. A high concentrated liquid rectal spray composition useful for the treatment of
constipation and bowel evacuation before investigational procedures or surgery
comprising,
a) High concentration of Bisacodyl and its pharmaceutically acceptable salts in an amount of 2% to 10% w/v;
b) unique blend of solvents in an amount of 5% to 80% w/v;
c) mucoadhesive polymers in an amount of 1% to 10% w/v; and
d) preservatives in an amount of 1% to 15% w/v;
along with other pharmaceutically acceptable excipients.
2. The high concentrated liquid rectal spray composition according to claim 1, wherein said unique blend of solvents are selected from group of triacetine, glycofurol, polyethylene glycol, propylene glycol, ethyl alcohol, cremophore ELP, solutol, transcutol, labrasol, capmul, captex, Benzyl alcohol, benzyl benzoate and ethyl oleate.
3. The high concentrated liquid rectal spray composition according to claim 1, wherein said mucoadhesive polymers are selected from group of polyvinyl pyrollidone K 30, Hydroxypropylmethyl cellulose, hydroxyethyl cellulose and hydroxypropylcellulose.
4. The high concentrated liquid rectal spray composition according to claim 1, wherein said preservatives are selected from group of sodium methyl paraben, sodium propyl paraben, sodium benzoate, benzyl alcohol, ethyl alcohol, benzalkonium chloride and potassium sorbate.
5. The high concentrated liquid rectal spray composition according to claim 1, wherein the pharmaceutically acceptable excipients are selected from group of preservatives, anti-oxidants, chelating agents, osmotic agents and permeation enhancers.

6. A process for preparation of high concentrated liquid rectal spray composition
comprising the steps of,
a) Weighing and mixing the solvents and preservatives in manufacturing vessel;
b) dissolving mucoadhesive polymers in solution of step (a) with continuous stirring; and
c) dissolving the active ingredient into step (a) with applying heat upto 50°C to 60°C.
7. The process for preparation of high concentrated liquid rectal spray composition
according to claim 6, wherein said process comprising the steps of,
a) Weighing and mixing solvents such as Triacetine, Glycofurol and preservative such as Benzyl alcohol in manufacturing vessel;
b) dissolving mucoadhesive polymer, Polyvinylpyrollidone K30 in solution of step (a) with continuous stirring; and
c) dissolving active ingredient Bisacodyl into step (a) with applying heat upto 50°C to 60°C
8. A liquid rectal spray dispenser to deliver the composition of claim 1.