DESC:FIELD OF INVENTION:
The present invention relates to a dual release composition of Ursodeoxycholic acid and a process for preparation thereof. The dual release composition is a bilayer tablet having immediate release layer and sustained release layer.
BACKGROUND:
Ursodeoxycholic acid (UDCA) is a medication used in the management and treatment of cholestatic liver disease. The use of UDCA in treating liver disease dates back more than a hundred years. UDCA is commonly used to treat patients with primary biliary cholangitis (PBC), an immune-mediated cholestatic liver disease characterized by the destruction of intrahepatic bile ducts. It is the only drug approved by the US Food and Drug Admisnitration to treat PBC. Studies suggest that UDCA can significantly delay the progression of liver cirrhosis in patients with early stages of PBC.
The application of UDCA extends to the treatment of non-cholestatic liver diseases, owing to its multiple modes of action, such as reducing the serum levels of toxic hydrophobic bile salts, stimulating the hepatobiliary excretion of xenobiotics via phase II and III detoxification processes, having antioxidant activity against oxidative stress, and exerting anti-apoptotic effects on signaling pathways, such as protein kinase C and mitogen-activated protein kinases (MAPKs).
Despite its extended usage, UDCA is known to have low absorption profile and bioavailability, UDCA has unfavorable physicochemical properties. For example, UDCA is practically insoluble in water with the aqueous solubility of 160 ìg/mL. The intestinal absorption of UDCA has also been found to be incomplete; reaching approximately 47.7% ± 9.0% for a 500 mg oral dose, and it has been reported to even decrease with an increased dose, at 19.6% ± 9.1% for a 1000 mg oral dose. The therapeutic effect of ursodeoxycholic acid is not dependent on blood drug concentration but is related to drug concentration in bile.
3
Thus the obvious defects of UDCA formulation are that the absorption rate is low. In addition, when UDCA is quickly released into intestinal tracts which results in higher concentration in short period of time and as absorption is also hindered, hence gastrointestinal disorder is found to occur. One way to solve the issue is by giving multiple low strength dosage in a day, but Meebard et. al., have reported that single and multiple dose UDCA have similar effects on liver biochemistry and biliary enrichment in cholestatic liver disease. Biochemical improvement appears to be related to biliary (but not serum) enrichment with UDCA. [DOI: 10.1016/s0168-8278(96)80293-5]
To overcome the issues associated with Immediate Release formulation of UDCA, modified or extended or sustained or prolonged release formulation of UDCA have been developed. Currently Sustained release or extended release capsule, tablet and suspension of UDCA are present in the market.
However, extended-release preparations also cause a slower or delayed onset of effect in patients, which is due to the slow build-up of the drug. Therefore, some patients may require an immediate-release preparation before taking the controlled-release preparation. Thus, there is a need for an UDCA pharmaceutical composition that will not only increase the bioavailability of UDCA immediately but also maintain the bioavailability for an extended period of time. Such a pharmaceutical composition needs to dissolve rapidly in a patient requiring immediate relief and at the same time, provide an extended therapeutic level of UDCA in the patient and have good patient compliance and be easy to manufacture. Thus there is an unmet need in the art for UDCA formulations that further improve the treatment efficacy of UDCA and also reduce the toxic side effects of the higher dosage of drug and formulation that improves the effective drug utilization, while accurately regulating the blood concentration levels.
4
OBJECTIVE:
The objective of the present invention is to provide a pharmaceutical composition comprising UDCA, wherein UDCA exhibits both immediate and extended or sustained drug release profile.
Another objective of the present invention is to provide a bilayer pharmaceutical composition comprising UDCA, wherein one layer exhibits an immediate release drug profile and the other layer exhibits extended or sustained drug release profile.
Another objective of the present invention is to provide a tablet-in-tablet pharmaceutical composition comprising an inner tablet and an outer tablet compressed over the inner tablet, wherein the inner tablet comprises UDCA exhibiting extended or sustained drug release profile and the outer tablet comprises of UDCA exhibiting immediate drug release profile.
Another objective of the present invention is to provide a capsule pharmaceutical composition comprising pellets exhibiting immediate drug release profile and pellets exhibiting extended drug release profiles.
SUMMARY OF THE INVENTION:
The present invention discloses a composition comprising UDCA, wherein UDCA exhibits immediate and extended drug release profile. The dual release formulation of the present invention can be formulated into a bilayer or multilayer or tablet-in-tablet or capsule formulation.
In an embodiment the present invention provides bilayer composition comprises an immediate release layer comprises effective amount of ursodeoxycholic acid (UDCA) and sustained release layer comprises effective amount of ursodeoxycholic acid (UDCA).
5
DETAILED DESCRIPTION OF INVENTION:
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to
6
those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
The term “pharmaceutical composition” refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc.
The term “pharmaceutically acceptable excipient” refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products.
The term “excipients” as used herein means a component of a pharmaceutical product that is not an active ingredient. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
The term “Extended release” or “sustained release” as used herein refers drug delivery system which releases the active agents in sustained or modified or extended for a prolonged period of time.
The term “immediate release” as used herein refers to drug delivery system which release the active agent immediately after administration of active agents,
In an embodiment the present invention provides a pharmaceutical composition which exhibits both immediate and extended release of the active agent, wherein the active agent is UDCA.
In another embodiment the present invention provides a pharmaceutical composition which exhibits dual drug release profile, wherein the dual drug release profiles are immediate and extended drug release profile of the active ingredient, wherein the active ingredient is UDCA.
7
In another embodiment the present invention provides a pharmaceutical composition which exhibits dual drug release profile, wherein the dual drug release profiles are immediate and sustained, wherein the active ingredient is UDCA and wherein the pharmaceutical composition is present in the form of bilayer tablet or multilayer tablet or Tablet-in-tablet or pellets in capsule or multilayer pellets in capsule.
In an embodiment the present invention provides a bilayer tablet composition which exhibits dual drug release profile, wherein one layer exhibits immediate release of the drug and wherein the other layer exhibits extended release of the drug, and wherein the drug is UDCA.
In an embodiment the present invention provides a bilayer tablet composition comprising an immediate drug release layer and Extended or sustained drug release layer, wherein the drug is UDCA.
In another embodiment the present invention provides a bilayer tablet composition comprising an immediate drug release layer and Extended drug release layer, wherein the immediate drug release layer comprises of pharmaceutically acceptable excipient that results in the immediate release of the drug and the extended release layer comprising pharmaceutically acceptable excipients that results in the extended release of the drug.
In an embodiment the immediate release layer of the bilayer tablet comprises of pharmaceutically acceptable excipients that results in the immediate release of the drug, wherein the pharmaceutically acceptable excipients are binders, diluents, disintegrant, lubricant, colorant, anti-adherent, coating agents, polymers, solvents and the likes thereof.
In an embodiment the extended or sustained release layer of the bilayer tablet comprises of pharmaceutically acceptable excipients that result in the extended release of the drug, wherein the pharmaceutically acceptable excipients are extended
8
release polymer or matrix forming agents, binders, diluents, disintegrant, lubricants, colorant, anti-adherent agents, coating agents, solvents and the likes thereof.
In an embodiment the present invention provides a tablet-in-tablet composition comprising an inner tablet and an outer tablet compressed over the inner tablet, wherein the inner tablet exhibits extended release of the drug and the outer tablet exhibits immediate release of the drug, wherein the drug is UDCA.
In another embodiment the inner tablet of the tablet-in-tablet composition comprises of pharmaceutically acceptable excipients that results in the Extended release of the drug, wherein the pharmaceutically acceptable excipients are Extended release polymers or matrix forming agents, diluents, binders, disintegrant, lubricants, anti-adherent agents, colorants, coating agents, surfactant, solvents, polymers and the likes thereof.
In another embodiment the outer tablet of the tablet-in-tablet composition comprises of pharmaceutically acceptable excipients that results in the immediate release of the drug, wherein the pharmaceutically acceptable excipients are diluents, binders, disintegrants, lubricants, anti-adhering agents, surfactants, solvents, colorants, coating agents, polymers and the likes thereof.
In another embodiment the present invention provides a pharmaceutical composition in the form of capsules, wherein the capsules comprise of pellets which exhibits immediate drug release profiles and pellets that exhibits Extended drug release profile, wherein the drug is UDCA.
In an embodiment the pellets exhibiting immediate drug release profile comprises of pharmaceutically acceptable excipient that results in the immediate release of the drug and wherein the pharmaceutically acceptable excipients are diluent, disintegrants, binders, solvents, lubricants, anti-adherent agents, coating agents, polymers, colorants and likes thereof.
9
In an embodiment the pellets exhibiting extended drug release profile comprises of pharmaceutically acceptable excipients that results in the extended release of the drug and wherein the pharmaceutically acceptable excipients are extended release polymers or matrix forming agents, diluent, disintegrants, binders, solvents, lubricants, anti-adherent agents, coating agents, polymers, colorants and the likes thereof.
In an embodiment the present invention provides a multilayer composition which exhibits both immediate and Extended release of the drug, wherein the drug is UDCA.
In another embodiment the UDCA of the present is optionally micronized or nanonized.
In another embodiment the present invention provides a pharmaceutical composition comprising micronized or nanonized UDCA, wherein the pharmaceutical composition exhibits both immediate and Extended drug release profile and wherein the pharmaceutical composition is present in the form of tablet, bilayer tablet, multilayer tablet, tablet-in-tablet, pellets, minitablets, and capsules.
In another embodiment the present invention provides a pharmaceutical composition comprising UDCA nanoparticles, wherein the pharmaceutical composition exhibits both immediate and Extended drug release profile and wherein the pharmaceutical composition is present in the form of a tablet, capsules, pellets, minitablets, bilayer tablets, multilayer tablets and tablet-in-tablet dosage forms.
In an embodiment the examples of diluents of the present invention are diluents that can be the conventional diluents in the field, including but not limited to one or more of calcium hydrogen phosphate, kaolin, dextrin, lactose, sucrose, microcrystalline cellulose, powdered cellulose, calcium carbonate, sorbitol powder, starch, starch derivatives, erythritol, xylitol and fructose, dextrin, lactose, microcrystalline cellulose and starch, more preferably one or more of dextrin, lactose and microcrystalline
10
cellulose The starch derivatives can be the conventional starch derivatives in the field, preferably including one or more of corn starch, potato starch, compressible starch, modified starch and pregelatinized starch.
In an embodiment the diluents are present in the range of 10% to 70% of the formulation
In an embodiment the example of disintegrants of the present invention are selected from but not limited to Calcium Alginate & Calcium Sodium Alginate, Microcrystalline Cellulose (MCC), Calcium carboxymethylcellulose / calcium cellulose glycolate / carmellose calcium, Powdered Cellulose, Chitosan Hydrochloride, Crospovidone, croscarmellose sodium, starch, potato starch, pregelatinized starch, com starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and combinations thereof.
In an embodiment the disintegrants are present in the range of 0.01% to 30% of the formulation
In an embodiment the examples of binders of the present invention are selected from but not limited to corn starch, polyvinyl pyrrolidone (PVP K12, K17, K25, K30, K60, K90, or K120), vinylpyrrolidone-vinylacetate copolymer (Copovidone) and cellulose derivatives like hydroxymethylcellutose, hydroxyethylcellulose, hydroxypropyl-cellulose and hydroxypropylmethylcellulose, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth, Sodium Carboxy Methyl Cellulose, Polyethylene Glycol (PEG) and Methylcellulose, Acacia, Calcium carboxymethylcellulose; calcium cellulose glycolate; carmellose calcium; Carbomer, Sorbitol, Maltodextrin, sucrose, Zein, Polyethylene Oxide, Magnesium Aluminum Silicate, Inulin, carbopol, xanthan gum, glucose solution, polyamylalcohol, waxes etc. and combinations thereof.
In an embodiment the binders are present in the range of 0.1% to 30% of the formulation.
11
In an embodiment the examples of extended release polymer or matrix forming agents of the present invention are selected from but not limited to hydroxyl propyl methyl cellulose (HPMC) and Hydroxyl propyl cellulose (HPC), Xanthan gum, Carbopol 940 and Alginates.
In an embodiment the Extended release polymer or matrix forming agent are present in the range of 0.01% to 20%.
In an embodiment the examples of lubricants of the present invention are selected from but not limited to magnesium stearate or alternatively calcium stearate, zinc stearate, aluminum stearate, sodium stearyl fumarate, talc, polyethylene glycol, stearic acid.
In an embodiment the lubricants are present in the range of 0.001% to 10%
In an embodiment the examples of anti-adherent agents of the present invention are selected from but not limited to silicon dioxide, calcium silicate is among the best performing antiadherents. Lubricants (salts of stearic acid or sodium stearyl fumarate), talc, leucine
In an embodiment the examples of coating agents of the present invention are coating agents that can be the conventional coating agents in the field.
In an embodiment the examples of polymer of the present invention are selected from but not limited to ethyl cellulose, HPMC, Starch, Gelatin, polyvinylpyrrolidine. Alginic acid, Glucose, Sucrose
In an embodiment the polymers are present in the range of 0.1% to 10%
In an embodiment the examples of solvents of the present invention are selected from but not limited to water, methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.
In an embodiment the present invention provides dual release composition comprises:
12
a. an immediate release layer comprises effective amount of ursodeoxycholic acid and;
b. a sustained release layer comprises effective amount of ursodeoxycholic acid
In a further embodiment the present invention provide bilayer pharmaceutical composition comprises:
a. an immediate release layer comprises ursodeoxycholic acid in an amount of about 50 to 90% based on total weight of immediate release layer and;
b. a sustained release layer comprises effective amount of ursodeoxycholic acid in an amount of about 50 to 90 % based on total weight of sustained release layer
in an embodiment the bilayer tablet comprising:
i. an immediate release layer comprising UDCA in an amount of about 67.52 % based on total weight of immediate release layer and;
ii. a sustained release layer comprising UDCA in an amount of about 73.58 % based on total weight of sustained release layer
in an another embodiment the immediate release layer further one or more pharmaceutical excipients selected from binders, diluents, fillers, lubricants, glidants, disintegrants, coloring agents, solubilizer.
In an embodiment the immediate release layer comprises one or more binders selected from corn starch, polyvinyl pyrrolidone (PVP K12, K17, K25, K30, K60, K90, or K120), vinylpyrrolidone-vinylacetate copolymer (Copovidone) and cellulose derivatives like hydroxymethylcellutose, hydroxyethylcellulose, hydroxypropyl-cellulose and hydroxypropylmethylcellulose, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth, Sodium Carboxy Methyl Cellulose, Polyethylene Glycol (PEG) and Methylcellulose, Acacia, Calcium carboxymethylcellulose; calcium cellulose glycolate; carmellose calcium.
13
In a preferred embodiment immediate release layer comprises Polyvinylpyrrolidone (PVPK-30) as binder present in an amount ranging from about 0.5 to 10 % based on total weight of immediate release layer.
In a further embodiment immediate release layer further comprises one or more diluent selected from calcium hydrogen phosphate, kaolin, dextrin, lactose, sucrose, microcrystalline cellulose, powdered cellulose, calcium carbonate, sorbitol powder, starch, starch derivatives, erythritol, xylitol and fructose, dextrin, lactose, microcrystalline cellulose and starch, more preferably one or more of dextrin, lactose and microcrystalline cellulose The starch derivatives can be the conventional starch derivatives in the field, preferably including one or more of corn starch, potato starch, compressible starch, modified starch and pregelatinized starch.
In an embodiment preferred diluents are combinations of starch, lactose and microcrystalline cellulose present in an amount ranging from 0.5 to 10% based on total weight of immediate release layer.
In a further embodiment immediate release layer further comprises one or more glidant selected from talcum, aluminium silicate, colloidal silica, starch or combinations thereof.
In an embodiment preferred glidants are combinations of Talcum and colloidal silica present in an amount ranging from 0.05 to 5 % based on total weight of immediate release layer.
In an embodiment preferred disintegrants are selected from Calcium Alginate & Calcium Sodium Alginate, Microcrystalline Cellulose (MCC), Calcium carboxymethylcellulose / calcium cellulose glycolate / carmellose calcium, Powdered Cellulose, Chitosan Hydrochloride, Crospovidone, croscarmellose sodium, starch, potato starch, pregelatinized starch, com starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and combinations thereof.
14
In a preferred embodiment preferred disintegrant is Sodium starch glycolate present in an amount of 2 to 10 % based on total weight of immediate release layer.
In a further embodiment an immediate layer comprises one or more solubilizer or surfactant selected from but not limited to Poloxamers, Polyoxyethylenesorbitan fatty acid esters, Miglyol, Labrafac, Polyoxyl 40 hydrogenated castor oil, Sodium lauryl sulfate, Cyclodextrins, Propylene glycol, vitamin E TPGS (tocophersolan), Sorbitan monooleate.
In a further embodiment preferred solubilizer/surfactant present in immediate release layer is Sodium lauryl sulphate present in an amount ranging from about 0.05 to 2% based on total weight of immediate release layer.
In an embodiment the immediate layer further comprises lubricant selected from magnesium stearate or alternatively calcium stearate, zinc stearate, aluminum stearate, sodium stearyl fumarate, talc, polyethylene glycol, stearic acid.
In a further embodiment preferred lubricant is magnesium stearate present in an amount of 1 to 5% based on total weight of immediate release layer.
The immediate layer of present invention comprises:
i. Ursodeoxycholic acid (UDCA) present in an amount of about 50 to 90% based on total weight of immediate release layer and;
ii. One or more binder presents in an amount of about 0.5 to 10 % based on total weight of immediate release layer and;
iii. One or more diluents present in an amount of about 0.5 to 10% based on total weight of immediate release layer and;
iv. One or more glidant present in an amount of about 0.05 to 5 % based on total weight of immediate release layer and;
v. One or more disintegrant present in an amount of 2 to 10 % based on total weight of immediate release layer.
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vi. One or more solubilizer/surfactant present in an amount of about 0.05 to 2% based on total weight of immediate release layer.
In an another embodiment the immediate release layer of bilayer tablet comprises:
i. UDCA present in an amount of about 67.52 % based on total weight of immediate release layer and;
ii. Combination of starch, lactose and microcrystalline cellulose present in an amount of about 7.353 %; 2.47% and 7.353% respectively as diluents and;
iii. Polyvinylpyrrolidone present in an amount of about 3.235 % as binder and;
iv. Talcum and colloidal silicon dioxide present in an amount of about 1.47% as glidant and;
v. Sodium starch glycolate present in an amount of about 5.88 % as disintegrant
vi. Sodium lauryl sulphate as solubilizer/surfactant present in an amount of about 0.88 % based on total weight of immediate release layer
In an another embodiment the sustained release layer comprises one or more excipients selected from group consisting of diluent, disintegrants, binders, solvents, lubricants, anti-adherent agents, coating agents, polymers, colorants and likes thereof.
In an embodiment sustained release layer comprises rate controlling polymer selected from but not limited to cellulose acetate phthalate, cellulose acetate succinate, hydroxpropyl cellulose phthalate, hydroxpropyl ethylcellulose phthalate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxyethyl cellulose phthalate, methylcellulose phthalate, hydroxypropyl methylcellulose, polyvinyl acetate phthalate, polyvinylacetate hydrogen phthalate, amylase acetate phthalate, cellulose ester phthalates, cellulose ether phthalates, sodium cellulose acetate phthalate, starch acid phthalate, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate propionate,
16
styrene maleic acid dibutyl phthalate copolymer, styrene maleic acid polyvinyl acetate phthalate copolymer propionate, shellac or combinations thereof.
In an another embodiment rate controlling polymer is Hydroxypropyl methylcellulose present in an amount ranging from 1 to 20% based on total weight of bilayer tablet.
In an embodiment the sustained release layer further comprises one or more diluent selected from group consisting of calcium hydrogen phosphate, kaolin, dextrin, lactose, sucrose, microcrystalline cellulose, powdered cellulose, calcium carbonate, sorbitol powder, starch, starch derivatives, erythritol, xylitol and fructose, dextrin, lactose, microcrystalline cellulose and starch.
In an another embodiment preferred diluent present in sustained release layer is microcrystalline cellulose present in an amount ranging from 2 to 20% based on total weight of sustained release layer.
In a further embodiment the sustained release layer further comprises one or more binder selected from corn starch, polyvinyl pyrrolidone (PVP K12, K17, K25, K30, K60, K90, or K120), vinylpyrrolidone-vinylacetate copolymer (Copovidone) and cellulose derivatives like hydroxymethylcellutose, hydroxyethylcellulose, hydroxypropyl-cellulose and hydroxypropylmethylcellulose, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth, Sodium Carboxy Methyl Cellulose, Polyethylene Glycol (PEG) and Methylcellulose, Acacia, Calcium carboxymethylcellulose; calcium cellulose glycolate, carmellose calcium or combinations thereof.
In an embodiment preferred binder present in sustained release layer is polyvinylpyrrolidine present in an amount ranging from 0.05 to 5% based on total weight of sustained release layer
In an another embodiment sustained release layer further comprises glidant selected from talcum, aluminum silicate, colloidal silicon dioxide, starch or combinations thereof.
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In an another embodiment preferred glidant is colloidal silicon dioxide present in an amount ranging from 2 to 10 % based on total weight of sustained release layer.
In an embodiment the present invention provides sustained release layer comprising:
a. Ursodeoxycholic acid (UDCA) present in an amount of about 50 to 90 % based on total weight of sustained release layer and;
b. One or more rate controlling polymer present in an amount of about 1 to 20% based on total weight of sustained release layer and;
c. One or more binder presents in an amount of about 0.05 to 5% based on total weight of sustained release layer and;
d. One or more diluent presents in an amount of about 1 to 20% based on total weight of sustained release layer and;
e. One or more glidant presents in an amount of about 1 to 10 % based on total weight of sustained release layer and;
f. One or more lubricant presents in an amount of about 1 to 5 % based on total weight of sustained release layer and;
In a further embodiment the present invention provides sustained release layer of bilayer tablet comprising:
a. UDCA present in an amount of about 73.58 % based on total weight of sustained release layer and;
b. Hydroxypropyl methylcellulose present in an amount of about 8.26 % in dry mix portion and 6.73 % in lubrication portion as rate controlling polymer and;
c. Microcrystalline cellulose present in an amount of about 6.61% as diluent and;
d. polyvinyl pyrrolidone present in an amount of about 1.92% as binder and;
e. colloidal silicon dioxide presents in an amount of about 1.44 % as glidant and;
f. magnesium stearate presents in an amount of about 1.44 % as lubricant
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In an embodiment the present invention provides method of preparing a bilayer tablet formulation comprises:
a. Preparing the immediate release layer by:
i. Sifting Ursodeoxycholic acid, lactose, starch and iron oxide to obtain a premix and;
ii. Dissolve polyvinyl pyrrolidone in purified water to obtain a binder solution and;
iii. The binder solution is added to premix in rapid mix granulator to obtain a desired consistency and;
iv. The wet mass obtained in step iii was passed through multi-mill and the wet coarse granules is collected in fluidized bed processor bowl. The wet granules are then dried and sifted and;
v. The dried and sifted granules are lubricated with talcum, sodium starch glycolate, colloidal silicon dioxide, sodium lauryl sulphate.
b. Preparing the extended release layer by:
i. Sifting Ursodeoxycholic acid, microcrystalline cellulose (MCC PH-102), hydroxylpropyl methylcellulose (Methocel K100 LV) and;
ii. Dissolve polyvinyl pyrrolidone in purified water to obtain a binder solution and;
iii. The sifted materials were mixed with binder solution in a rapid mixing granulator to obtain a desired consistency and;
iv. The wet mass obtained in step iii was passed through multi-mill and the wet coarse granules is collected in fluidized bed processor bowl. The wet granules are then dried and sifted and;
v. The dried and sifted granules are lubricated with colloidal silicon dioxide, magnesium stearate and hydroxylpropyl methylcellulose (Methocel K100 LV)
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c. Performing a compression step to form the bilayer tablets
This invention is further defined by reference to the following example. Although the example is not intended to limit the scope of the present invention, it should be considered in the light of the description detailed above. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
Example-1
S.NO
Ingredient
Mg / Tab
%
Role
Part-I (I.R Form)
DRY MIX
1
Ursodeoxycholic acid
229.570
67.521
API
2
Lactose
8.430
2.479
Diluent
3
Starch (Maize)
25.00
7.353
diluent
4
Iron oxide (ferric oxide)
1.00
0.294
colorant
BINDER
5
Polyvinylpyrrolidone (PVPK-30)
11.00
1.279
Binder
6
Purified Water
QS
Solvent
LUBRICATION
7
Talcum
5.00
1.471
Glidant
8
Microcrystalline cellulose
(M.C.C PH-102)
25.00
7.353
Diluent
9
Sodium starch glycolate
20.00
5.882
Disintegrant
10
Colloidal silicon dioxide
5.00
1.471
Glidant
11
Sodium lauryl sulphate
3.00
0.882
Surfactant
12
Magnesium stearate
7.00
2.059
Lubricant
TOTAL
340
100.00
Part-II (S.R Form)
20
DRY MIX
1
Ursodeoxycholic acid
382.61
73.580
API
2
Microcrystalline cellulose
(M.C.C PH-102)
34.390
6.613
Diluent
3
Hydroxypropyl methylcellulose (METHOCEL K4 M)
43.00
8.269
Release controller
BINDER
4
Polyvinylpyrrolidone (PVPK-30)
10.00
1.923
Binder
5
Purified water
LUBRICATION
6
Hydroxypropyl methylcellulose (METHOCEL K100 LV)
35
6.731
Release controller
7
Colloidal silicon dioxide
7.5
1.442
Glidant
8
Magnesium stearate
7.5
1.442
Lubricant
TOTAL
520.00
100.00
Example-2: Process of preparing UDCA bilayer tablet
a. Preparing the immediate release layer by:
i. Sifting Ursodeoxycholic acid, lactose, starch and iron oxide to obtain a premix and;
ii. Dissolve polyvinyl pyrrolidone in purified water to obtain a binder solution and;
iii. The binder solution is added to premix in rapid mix granulator to obtain a desired consistency and;
iv. The wet mass obtained in step iii was passed through multi-mill and the wet coarse granules is collected in fluidized bed processor bowl. The wet granules are then dried and sifted and;
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v. The dried and sifted granules are lubricated with talcum, sodium starch glycolate, colloidal silicon dioxide, sodium lauryl sulphate.
b. Preparing the extended release layer by:
i. Sifting Ursodeoxycholic acid, microcrystalline cellulose (MCC PH-102), hydroxylpropyl methylcellulose (Methocel K100 LV) and;
ii. Dissolve polyvinyl pyrrolidone in purified water to obtain a binder solution and;
iii. The sifted materials were mixed with binder solution in a rapid mixing granulator to obtain a desired consistency and;
iv. The wet mass obtained in step iii was passed through multi-mill and the wet coarse granules is collected in fluidized bed processor bowl. The wet granules are then dried and sifted and;
v. The dried and sifted granules are lubricated with colloidal silicon dioxide, magnesium stearate and hydroxylpropyl methylcellulose (Methocel K100 LV)
c. Performing a compression step to form the bilayer tablets

,CLAIMS:1. A dual release pharmaceutical composition comprising effective amount of Ursodeoxycholic acid (UDCA).
2. A dual release pharmaceutical composition as claimed in claim 1 wherein dual release composition is present in form of bilayer tablet or multilayer tablet or Tablet-in-tablet or pellets in capsule or multilayer pellets in capsule.
3. A dual release pharmaceutical composition as claimed in 2, wherein dual release composition is bilayer tablet comprising immediate release layer and sustained release layer.
4. A bilayer tablet as claimed in claim 3 comprises:
i. an immediate release layer comprising UDCA in an amount of about 50 to 90% based on total weight of immediate release layer and;
ii. a sustained release layer comprising UDCA in an amount of about 50 to 90 % based on total weight of sustained release layer.
5. An immediate release layer as claimed in claim 4 comprises:
i. Ursodeoxycholic acid (UDCA) present in an amount of about 50 to 90% based on total weight of immediate release layer and;
ii. One or more binder presents in an amount of about 0.5 to 10 % based on total weight of immediate release layer and;
iii. One or more diluents present in an amount of about 0.5 to 10% based on total weight of immediate release layer and and;
iv. One or more glidant present in an amount of about 0.05 to 5 % based on total weight of immediate release layer and;
v. One or more disintegrant present in an amount of 2 to 10 % based on total weight of immediate release layer and;
vi. One or more solubilizer/surfactant present in an amount of about 0.05 to 2% based on total weight of immediate release layer
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6. An immediate release layer as claimed in claim 4 comprises:
i. UDCA present in an amount of about 67.52 % based on total weight of immediate release layer and;
ii. Combination of starch, lactose and microcrystalline cellulose present in an amount of about 7.35 %; 2.47% and 7.35% respectively based on total weight of immediate release layer as diluent and;
iii. Polyvinylpyrrolidone present in an amount of about 3.23 % based on total weight of immediate release layer as binder and;
iv. Talcum and colloidal silicon dioxide present in an amount of about 1.47 % based on total weight of immediate release layer as glidant and;
v. Sodium starch glycolate present in an amount of about 5.88% based on total weight of immediate release layer as disintegrant and;
vi. Sodium lauryl sulphate as solubilizer/surfactant present in an amount of about 0.88 % based on total weight of immediate release layer based on total weight of immediate release layer
7. A sustained release layer as claimed in claim 6 comprises:
i. Ursodeoxycholic acid (UDCA) present in an amount of about 50 to 90% based on total weight of sustained release layer and;
ii. One or more rate controlling polymer present in an amount of about 1 to 20% based on total weight of sustained release layer and;
iii. One or more binder presents in an amount of about 0.05 to 5% based on total weight of sustained release layer and;
iv. One or more diluent presents in an amount of about 1 to 20% based on total weight of sustained release layer and;
v. One or more glidant presents in an amount of about 1 to 10% based on total weight of sustained release layer and;
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vi. One or more lubricant presents in an amount of about 1 to 5 % based on total weight of sustained release layer
8. A sustained release layer as claimed in claim 7 comprises:
i. UDCA present in an amount of about 73.58% based on total weight of sustained release layer and;
ii. Hydroxypropyl methylcellulose present in an amount of about 8.26 % in dry mix portion and 6.73 % based on total weight of sustained release layer in lubrication portion as rate controlling polymer and;
iii. Microcrystalline cellulose present in an amount of about 6.61% based on total weight of sustained release layer as diluent and;
iv. polyvinyl pyrrolidone present in an amount of about 1.92 % based on total weight of sustained release layer as binder and;
v. colloidal silicon dioxide presents in an amount of about 1.44 % based on total weight of sustained release layer as glidant and;
vi. magnesium stearate presents in an amount of about 1.44 % based on total weight of sustained release layer as lubricant
9. A method of preparing bilayer tablet composition as claimed in claim 1-7 comprises following steps:
a. Preparing the immediate release layer by:
i. Sifting Ursodeoxycholic acid, lactose, starch and iron oxide to obtain a premix and;
ii. Dissolve polyvinyl pyrrolidone in purified water to obtain a binder solution and;
iii. The binder solution is added to premix in rapid mix granulator to obtain a desired consistency and;
iv. The wet mass obtained in step iii was passed through multi-mill and the wet coarse granules is collected in fluidized bed processor bowl. The wet granules are then dried and sifted and;
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v. The dried and sifted granules are lubricated with talcum, sodium starch glycolate, colloidal silicon dioxide, sodium lauryl sulphate.
b. Preparing the extended release layer by:
i. Sifting Ursodeoxycholic acid, microcrystalline cellulose (MCC PH-102), hydroxylpropyl methylcellulose (Methocel K100 LV) and;
ii. Dissolve polyvinyl pyrrolidone in purified water to obtain a binder solution and;
iii. The sifted materials were mixed with binder solution in a rapid mixing granulator to obtain a desired consistency and;
iv. The wet mass obtained in step iii was passed through multi-mill and the wet coarse granules is collected in fluidized bed processor bowl. The wet granules are then dried and sifted and;
v. The dried and sifted granules are lubricated with colloidal silicon dioxide, magnesium stearate and hydroxylpropyl methylcellulose (Methocel K100 LV)
3. Performing a compression step to form the bilayer tablets.