DESC:PHARMACEUTICAL TABLET FORMULATION CONTAINING NANO SIZED URSODEOXYCHOLIC ACID (UDCA NANO) AND THE METHOD OF ITS PREPARATION
FIELD OF THE INVENTION:
The present invention relates to pharmaceutical formulation in tablet form, containing nano sized Ursodeoxycholic acid (hereinafter referred as UDCA Nano) and the method of its preparation, wherein said formulation is characterized in its higher aqueous dispersibility & solubility and comparatively faster rate of metabolization into the blood stream leading to easily achieving the optimum blood levels. More particularly, the present invention discloses a chemical composition in the form of nano-sized Ursodeoxycholic acid (UDCA Nano) containing tablets and the process for its preparation.
The present invention more particularly relates to preparation of Ursodeoxycholic acid (Nano grade) tablets 10mg and 300mg, wherein the parameters of stiffness to develop the said Ursodeoxycholic acid (Nano grade) tablets are standardized for better bioavailability and better therapeutic effects. It is an immediate release (IR) tablet, indicated for showing efficacy toward improving the conditions of gallstones, cholecystitis, PBC & PSC in an individual.
The scope of this disclosure is mainly limited to development of Ursodeoxycholic acid (Nano grade) tablets 10mg and 300 mg and evaluation of the same to develop the production batch.

BACKGROUND AND OBJECT OF THE INVENTION:
General information about the chemical compound Ursodeoxycholic acid:

There are few prior arts available which discuss about ursodeoxcycholic acid and its uses, as indicated above.
As per the abstract of a prior publication in “Informa Healthcare”, 2014 titled “Protective efficacy of ursodeoxcycholic acid nanoparticles in animal model of inflammatory bowel disease” by A K De, S Sana, S Datta, A Mukharjee, SRIPARNA DUTTA:-
Context: Ursodeoxycholic acid (UDCA) exerts dose-dependent chemoprevention in colonic inflammation. Polycationic UDCA nanoparticles (UNPs) are envisaged for solubility enhancement and site directed drug delivery. Objective: The objective was to study the ameliorative efficacy of UNPs through localized delivery of the drug. Methods: UNPs were prepared through nanoprecipitation technique. Particle size, morphology, in vitro drug release and in vivo protective efficacy in inflammatory bowel disease (IBD) of these nanoparticles were studied. Results and Discussion: The average particle size was around 100?nm, and the average drug encapsulation was about 99%. In vitro drug release study shows optimal drug release in simulated colonic fluid. The lowering of tissue nitric oxide, malondialdehyde, myeloperoxidase and histology of the colon tissue supported the protective efficacy of the nanoparticles. Conclusion: This study presents the improved efficacy of UNPs in animal model of IBD due to complete release of drug at the desired site of action.
Another prior art CN101606906A titled “Ursodeoxycholic acid nano suspension and preparation method thereof” describes about Ursodeoxycholic acid nano suspension of the present invention and preparation method thereof relates to the medicament nano-preparation field, be specifically related to treat the Ursodeoxycholic acid nano suspension and the dried powder thereof of cholestasis liver cirrhosis, it is characterized in that adopting SDS and PVP K30 as surfactant, and SDS and PVP K30 are with weight ratio combination in 1: 1~1: 3, Ursodeoxycholic acid nano suspension steady quality of the present invention, particle diameter is about 200~800nm, the invention also discloses its preparation method.
Thus it is presumed that Ursodeoxycholic acid in nano sized composition are known to the persons skilled in the art. However, there is still the requirement of more efficacious tablet compositions of Ursodeoxycholic acid in nano-grade, which is capable of getting metabolized in the blood stream faster towards easily achieving the optimum blood levels as well as faster recovery of patients.
Prime object invention is to provide pharmaceutical formulation in tablet form, containing nano sized Ursodeoxycholic acid (UDCA Nano) and the method of its preparation, wherein said formulation is characterized in its higher aqueous dispersibility & solubility and comparatively faster rate of metabolization into the blood stream leading to easily achieving the optimum blood levels.
Another object is to provide effective method for bulk manufacturing of the pharmaceutical tablet formulation, containing nano sized Ursodeoxycholic acid (UDCA Nano) as main active component; wherein said pharmaceutical tablet formulation is characterized in its higher aqueous dispersibility & solubility and comparatively faster rate of metabolization into the blood stream leading to easily achieving the optimum blood levels.
Another object of the present invention is to provide a method for preparation of Ursodeoxycholic acid (Nano grade) tablets 10mg and 300mg, wherein the parameters of stiffness to develop the said Ursodeoxycholic acid (Nano grade) tablets are standardized for better bioavailability and better therapeutic effects.

SHORT DETAILS OF THE DRAWINGS:
Figure 1: Represents schematic general plan for bulk manufacturing of the pharmaceutical tablet formulation in tablet form, containing nano sized Ursodeoxycholic acid (UDCA Nano), showing the steps to be performed one-after-another.
Figure 2: Represents second schematic plan for bulk manufacturing of the pharmaceutical tablet formulation in tablet form, containing nano sized Ursodeoxycholic acid (UDCA Nano).

SUMMARY OF THE INVENTION:
The present invention is more specifically for the product Ursodeoxycholic acid tablets in a nano grade form, formulation and process for its preparation.
When particle size of the molecule is reduced to Nano Size, it gets metabolizes in the blood stream faster and optimum blood levels are easily achieved. It has Higher and faster recovery of patients. The formulation of this invention has the potential to be used to be used for Treatment of Liver diseases. The product as per this invention is superior solution to existing General Methodology
The invention comprises Ursodeoxycholic acid (UDCA), C24H40O4 ,as the active ingredient in a tablet formulation wherein said compound UDCA has been reduced to Nano Size particles (UDCA Nano) and then medicinal formulation is made and its efficacy is analysed.
UDCA is otherwise absorbed incompletely because of its low aqueous solubility.
As per the invention, the tablet could be achieved in different release formulation. It is preferably in an immediate release tablet indicted for treatment of gallstones, cholecystitis, PBC and PSC and stuffiness. The bioavailability as well as the Therapeutic effect of the instant (UDCA Nano) containing tablet formulation is better. The Ursodeoxycholic acid tablets in a nano grade form are stable with higher shelf life. The tablet as per the invention may be administered in various dosage forms from 1 mg to 500 mg, preferably at 150 mg and 300 mg.
Different known excipients in different ratios, are used in for the formulation of Ursodeoxycholic acid tablets in a nano grade form as per the invention.
Different ingredients and excipients in various ratios along with Ursodeoxycholic acid (UDCA Nano) are to be used in preparation of the formulation as per the invention which also include optionally selected pharmaceutically acceptable excipients, selected from Starch, Sodium starch Glycolate, Lactose, Polyvinyl Pyrrolidone K-30, Sodium Lauryl Sulphate, Magnesium Stearate, Talc, Colloidal Silicon Dioxide, Cross Povidone XL 10, Kyron T-314. Various ingredients perform different roles in the formulation which include that of being the Active Ingredient, Diluent, Disintegrant, Binder, Solublizer, Lubricant, Glider.
Various identification methods are used in identifiction of the ingredients used in preparation of formulation as per the present invention which include identification of the drug substance by IR, HPLC and other methods.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention is more specifically for the product Ursodeoxycholic acid tablets in a nano grade form, formulation and process for its preparation.
When particle size of the molecule is reduced to Nano Size, it gets metabolizes in the blood stream faster and optimum blood levels are easily achieved. It has Higher and faster recovery of patients. The formulation of this invention has the potential to be used to be used for Treatment of Liver diseases.
The product as per this invention is superior solution to existing General Methodology.
The invention comprises a drug, Ursodeoxycholic acid (UDCA), C24H40O4 ,a bulk drug which is reduced to Nano Size particles (UDCA Nano) and then medicinal formulation is made.
UDCA is otherwise absorbed incompletely because of its low aqueous solubility.
As per the invention, the tablet could be achieved in different release formulation. It is preferably in an immediate release tablet indicted for treatment of gallstones, cholecystitis, PBC and PSC and stuffiness. The bioavailability is better. Therapeutic effect is better. The Ursodeoxycholic acid tablets in a nano grade form are stable in tablet form with shelf life.
The tablet as per the invention may be administered in various dosage forms from 1 mg to 500 mg, preferably at 150 mg and 300 mg.
Different known excipients in different ratios, are used in for the formulation of Ursodeoxycholic acid tablets in a nano grade form as per the invention.
Different ingredients and pharmaceutically acceptable excipients in various ratios along with Ursodeoxycholic acid (UDCA Nano) are to be used in preparation of the formulation as per the invention which also include Starch, Sodium starch Glycolate, Lactose, Polyvinyl Pyrrolidone K-30, Sodium Lauryl Sulphate, Magnesium Stearate, Talc, Colloidal Silicon Dioxide, Cross Povidone XL 10, Kyron T-314. Various ingredients perform different roles in the formulation which include that of being the Active Ingredient, Diluent, Disintegrant, Binder, Solublizer, Lubricant, Glider.
Various identification methods are used in identifiction of the ingredients used in preparation of formulation as per the present invention which includes identification of the pharmacetical substance by IR, HPLC and other methods.

Relating to preparation of preferred embodiment of the pharmaceutical tablet formulation containing nano sized Ursodeoxycholic acid (UDCA nano) and analysis of its biological/pharmaceutical efficacy:










In one embodiment of the invention, in order to prepare a batch size with 4,00,000 tablets, the ratio of various ingredients in the formulation and the quantity is given in below Table-1. It is understood that the ratio and weight of the ingredients could be suitably adapted which will not digress from the present invention.
Table-1
Sr. No. Name of Ingredients Spec. mg/tab Qty/batch kg.
1. Ursodeoxycholic acid IP 304.500 121.800
2. Starch IP 100.000 40.000
3. Sodium starch Glycolate IP 20.000 8.000
4. Lactose IP 80.000 32.000
5. Polyvinyl Pyrrolidone K-30 IP 15.000 6.000
6. Starch IP 10.000 4.000
7. Sodium Lauryl Sulphate IP 3.000 1.200
8. Magnesium Stearate IP 3.000 1.200
9. Purified Talc IP 3.000 1.200
10. Colloidal silicon dioxide IP 3.000 1.200
11. Cross Povidone XL 10 IP 5.200 2.080
12. Tulsion 339 (Kyron T-314) IH 5.200 2.080
13. Sodium starch glycolate IP 10.000 4.000

Potency calculation: It i done based on Standard Assay and Standard LOD
Details of the manufacturing process involved:
Shifting and Granulation
Sifting: Equipment used: (1) Electronic Balance (2) Mechanical Sifter

Towards the method of bulk manufacturing of the pharmaceutical formulation in tablet form, containing nano sized Ursodeoxycholic acid (UDCA Nano), various steps are designed and performed one-after-another, as under:
i. Sifted all the ingredients through the sieve of the mesh and collected the material in the polythene bags tagged with identification label.
ii. Passed Ursodeoxycholic acid (Nanoparticles) through 60# no. sieves and collected in a polybag.
iii. Sifted starch, sodium starch glycolate and Starch through 40# no. sieves.
iv. Dissolved PVP K-30 in purified water and prepareed binder solution.
v. Dry Mixing: Loaded the sifted materials from step no. (iii) & (iv) in rapid mixer granulator and mixed at slow speed for 15 minutes.
vi. Added binder in dry mix and prepared granules.
vii. Shifted step (vi) in fluid bed dryer for 60 min.
viii. Sifted the dried granules through sieve 30# and passed oversized granules through multimill fitted with 1.5mm screen.
ix. Fitted 60# no. sieves in vibro shifter and shifted the material mentioned below.
x. Sifted colloidal silicon dioxide, purified talc, Kyron T-314, Cross povidone XL 10 and Sodium starch glycolate mix in a polybag.
xi. Mixed step (x) with dried granules (step (viii)) for 15 minutes in octagonal blender.
xii. Sifted magnesium stearate through 60# sieve and mixed with step (xi) for 5 minutes. Thus the blend became ready for compression.
xiii. The rotary compression machine was set with die-punch set for the product. For example:
Punch Dimension:
• Ursodeoxycholic acid tablets 150 mg – 8.75 mm to 9.25 mm round both side plain.
• Ursodeoxycholic acid tablets 300 mg – 12.25mm to 12.75 mm, round, biconcave both side plaint.

b. Container Closure System
Ursodeoxycholic acid tablets IP 300 mg is packed in PVC blister pack.
c. Chemical Attributes: Specification and Method of Analysis for Finished Product: Specification for Ursodeoxycholic acid tablets IP 300 mg


It will be apparent to those skilled in the art that various modifications and variations can be made in the scheme(s), programming of various software based instructions involved, modules provisioned for data analysis and transmission/storage involved, or other possible arrangements and rearrangements within the present invention, without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention provided they come within the scope of the description, illustrations, drawings, appended claims and their equivalents.

,CLAIMS: A pharmaceutical tablet formulation and the method of its preparation, wherein said formulation comprises nano sized Ursodeoxycholic acid (UDCA Nano) and optionally selected excipients, which is characterized in its higher aqueous dispersibility & solubility and comparatively faster rate of metabolization into the blood stream leading to easily achieving the optimum blood levels.
2. The pharmaceutical tablet formulation, as claimed in claim 1, wherein said formulation involves the followings steps of the method of its bulk manufacturing:

3. The pharmaceutical tablet formulation, as claimed in claim 1, wherein the most preferred method for the preparation of tablets having nano-grade form of Ursodeoxycholic acid, involve the following steps, one followed by another, as under:
i. Sifted all the ingredients through the sieve of the mesh and collected the material in the polythene bags tagged with identification label.
ii. Passed Ursodeoxycholic acid (Nanoparticles) through 60# no. sieves and collected in a polybag.
iii. Sifted starch, sodium starch glycolate and Starch through 40# no. sieves.
iv. Dissolved PVP K-30 in purified water and prepareed binder solution.
v. Dry Mixing: Loaded the sifted materials from step no. (iii) & (iv) in rapid mixer granulator and mixed at slow speed for 15 minutes.
vi. Added binder in dry mix and prepared granules.
vii. Shifted step (vi) in fluid bed dryer for 60 min.
viii. Sifted the dried granules through sieve 30# and passed oversized granules through multimill fitted with 1.5mm screen.
ix. Fitted 60# no. sieves in vibro shifter and shifted the material mentioned below.
x. Sifted colloidal silicon dioxide, purified talc, Kyron T-314, Cross povidone XL 10 and Sodium starch glycolate mix in a polybag.
xi. Mixed step (x) with dried granules (step (viii)) for 15 minutes in octagonal blender.
xii. Sifted magnesium stearate through 60# sieve and mixed with step (xi) for 5 minutes, and the blend became ready for compression.
xiii. The rotary compression machine was set with die-punch set for the product.
4. The pharmaceutical tablet formulation, as claimed in claim 1, wherein the most preferred method for the preparation of tablets having nano-grade form of Ursodeoxycholic acid involve optionally selected Punch Dimension, namely:
• Ursodeoxycholic acid tablets 150 mg – 8.75 mm to 9.25 mm round both side plain
or
• Ursodeoxycholic acid tablets 300 mg – 12.25mm to 12.75 mm, round, biconcave both side plaint.
5. The pharmaceutical tablet formulation, as claimed in claim 1; wherein the excipients used in the said formulation is optionally selected from Starch, Sodium starch Glycolate, Lactose, Polyvinyl Pyrrolidone K-30, Sodium Lauryl Sulphate, Magnesium Stearate, Talc, Colloidal Silicon Dioxide, Cross Povidone XL 10, Kyron T-314.
6. The pharmaceutical tablet formulation, as claimed in claim 1; wherein in order to prepare a batch size with 4,00,000 tablets, the ratio of various ingredients in the formulation and the quantity is given in the Table-1, as under:
Table-1
Sr. No. Name of Ingredients Spec. mg/tab Qty/batch kg.
1. Ursodeoxycholic acid IP 304.500 121.800
2. Starch IP 100.000 40.000
3. Sodium starch Glycolate IP 20.000 8.000
4. Lactose IP 80.000 32.000
5. Polyvinyl Pyrrolidone K-30 IP 15.000 6.000
6. Starch IP 10.000 4.000
7. Sodium Lauryl Sulphate IP 3.000 1.200
8. Magnesium Stearate IP 3.000 1.200
9. Purified Talc IP 3.000 1.200
10. Colloidal silicon dioxide IP 3.000 1.200
11. Cross Povidone XL 10 IP 5.200 2.080
12. Tulsion 339 (Kyron T-314) IH 5.200 2.080
13. Sodium starch glycolate IP 10.000 4.000