FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENT RULE, 2003
COMPLETE SPECIFICATION (See section 10; rule 13)
“AN AQUEOUS SOLUTION OF CHOLECALCIFEROL”
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at SUN
HOUSE, 201 B/1, WESTERN EXPRESS HIGHWAY, GOREGAON (E),
MUMBAI-400063 MAHARASHTRA, INDIA.
The following specification particularly describes the invention and the manner in which it is to be performed.

Description
Title of Invention: AN AQUEOUS
SOLUTION OF CHOLECALCIFEROL
Technical Field
The present invention relates to an aqueous composition of cholecalciferol. The composition comprises a therapeutically effective amount of cholecalciferol and pharmaceutically acceptable excipients. In particular, the present invention relates to an oil-free, stable, aqueous composition of cholecalciferol at a concentration ranging from 400 IU-600000 IU. The invention also includes process of preparing such compositions and use of such compositions for the treatment and prevention of vitamin D deficiency. Background Art
Vitamin D deficiency has been associated with numerous health outcomes, including risk of rickets in children or osteomalacia in adults, increased risk of fractures, falls, cancer, autoimmune disease, infectious disease, type 1 and type 2 diabetes, hypertension and heart disease, and other diseases such as multiple sclerosis. The major cause of vitamin D deficiency is the lack of sun exposure which is the major source of vitamin D for most humans. Inadequate Vitamin D supply often develops in individuals who are infrequently exposed to sunlight with protective sunscreens, have chronically inadequate intakes of Vitamin D or, low calcium intake in conjunction with vitamin D deficiency makes matters worse.
The American Association of Clinical Endocrinologists has described vitamin D deficiency as 25 hydroxycholecalciferol (25 HCC) levels below 20 ng/ml (50 nmol/L). Based on the current guidelines in practice, Medical Journal Armed Forces India, 79 (1), 2023 indicates that approximately 90% of the healthy Indian population is vitamin D deficient. Therefore, the need for improvement in vitamin D status of the Indian population is both important and urgent.
Vitamin D3 (cholecalciferol) is used for the treatment of vitamin D deficiency and for the prevention or treatment of various medical conditions associated with vitamin D deficiency. Vitamin D3 can be taken either orally or by intramuscular injection. Oral liquid formulations are gaining increasing significance in context of improving patient compliance, particularly in comparison to conventional solid dosage forms, such as capsules and tablets, which are the most commonly used for oral administration. Several oral nanodispersion solution compositions of cholecalciferol are marketed in India such as Deksel (marketed by Pulse), Depura (marketed by Sanofi), Arachitol

(marketed by Abbott). Further, few oral liquid compositions of cholecalciferol have already been disclosed in the literature.
The nanoemulsions, microemulsion and nanodispersions compositions comprises certain amount of oil to incorporate cholecalciferol in the composition. However, developing oily composition with optimal particle size and high drug entrapment in dispersed phase is an outstanding challenge. Additionally, this composition are thermodynamic ally unstable systems that results in physical instability of drug entrapped in oil-phase, impeding the biological performance of a drug product.
Vitamin D3 is highly sensitive to oxygen and light, making them prone to oxidative degradation and loss of integrity when exposed to light, further posing challenges for high-dosage formulations. This instability limits the effectiveness of current approaches in preserving Vitamin D in oily compositions. Therefore, there is a need for a stable aqueous composition comprising cholecalciferol. There have been a few attempts in the literature, which are outlined as follows.
US 5182274 discloses an intravenous aqueous composition comprising the active form of Vitamin D3, a surface-active agent, an antioxidant, and at least one chelating agent.
US 4308264A discloses a diluted, stable, oral composition of lcc,25-dihydroxycholecalciferol to prevent hypocalcemia in neonates. This is an aqueous solution comprising nonionic surfactant and stabilized with a combination of a metal ascorbate and a chelating agent in the presence of an inert atmosphere at pH 6.4 to 7.8.
While above-mentioned compositions address the drawbacks of oil-based composition, none of them is stable for a longer period of time. Thus, an aqueous, oil-free compositions of Vitamin D3 have been strongly desired for oral administration to overcome the limitations such as poor stability and change in biological performance associated with other oral formulations. Summary of Invention
The present invention provides an aqueous composition comprising, cholecalciferol and pharmaceutically acceptable excipients, wherein the composition is stable for at least 6 months at 25 + 2°C / 60 + 5% RH.
In one embodiment, the present invention provides an oral, aqueous solution comprising therapeutically effective amount of cholecalciferol and pharmaceutically acceptable excipients, wherein the composition is stable for at least 6 months at 25 + 2°C / 60 + 5% RH.
In another embodiment, the present invention provides an aqueous, oral solution comprising,
a. therapeutically effective amount of cholecalciferol and,

b. pharmaceutically acceptable excipients.
In another embodiment, the present invention provides an aqueous, oral solution comprising,
a. cholecalciferol at a concentration in the range of 400 IU - 600000 IU and,
b. pharmaceutically acceptable excipients.
In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration of 54000 IU - 120000 IU and,
b. pharmaceutically acceptable excipients.
In another embodiment, the present invention provides an aqueous, oral solution comprising,
a. therapeutically effective amount of cholecalciferol,
b. a surfactant, and
c. a solubilizing agent.
In another embodiment, the present invention provides an oral, aqueous solution cholecalciferol comprising,
a. cholecalciferol at a concentration in the range of 400 IU-120000 IU,
b. a surfactant, and
c. a solubilizing agent.
In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration of 54000 IU - 120000 IU and,
b. a surfactant, and
c. a solubilizing agent.
In one aspect, the surfactant is a polyoxyethylene- polyoxypropylene block copolymers. In another preferred aspect, the surfactant is poloxamer.
In another aspect, the solubilizing agent is polyethylene glycol derivatives of vitamin E. In another preferred aspect, the solubilizing agent is vitamin E polyethylene glycol succinate.
In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration of 60000 IU and,
b. a surfactant, and
c. a solubilizing agent.
In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration in the range of 400 IU-120000 IU,
b. a surfactant, and

c. a solubilizing agent in an amount of 0.01% w/v - 3.00 % w/v.
In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration in the range of 400 IU-120000 IU,
b. a surfactant surfactant in an amount of about 0.01% w/v to 5 % w/v, and
c. a solubilizing agent.
In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration in the range of 400 IU-120000 IU,
b. a surfactant in an amount of about 0.01% w/v to 5 % w/v, and
c. a solubilizing agent in an amount of 0.01% w/v to 3 % w/v.
In another embodiment, the present invention provides an oral, aqueous solution of cholecalciferol comprising,
a. cholecalciferol at a concentration in the range of 400 IU-120000 IU,
b. a surfactant, and
c. Vitamin E polyethylene glycol succinate in an amount of 0.01% w/v to 3 %
w/v.
In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration in the range of 400 IU-120000 IU,
b. a surfactant,
c. a solubilizing agent, and
d. an antioxidant.
In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration in the range of 400 IU-120000 IU,
b. a surfactant,
c. a solubilizing agent, and
d. an antioxidant,
wherein the solution is stable for at least 6 months at 25 + 2°C / 60 + 5% RH. In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration in the range of 400 IU-120000 IU,
b. a surfactant,
c. a solubilizing agent, and
d. an antioxidant in an amount of about 0.001% w/v to 1 % w/v,
wherein the solution is stable for at least 6 months at 25 + 2°C / 60 + 5% RH.

In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration in the range of 400 IU-120000 IU,
b. a surfactant in an amount of about 0.01% w/v to 5 % w/v,
c. a solubilizing agent in an amount of about 0.01% w/v to 3 % w/v, and
d. an antioxidant in an amount of about 0.001% w/v to 1% w/v.
In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration in the range of 400 IU-120000 IU,
b. a surfactant in an amount of about 0.01% w/v to 5 % w/v,
c. a solubilizing agent in an amount of about 0.01% w/v to 3 % w/v, and
d. an antioxidant in an amount of about 0.001% w/v to 1% w/v,
wherein the solution is stable for at least 6 months at 25 + 2°C / 60 + 5% RH.
In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration in the range of 400 IU-120000 IU,
b. a surfactant, and
c. a solubilizing agent,
wherein, the pH of the solution ranges between 3.8-5.7.
In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration in the range of 400 IU-120000 IU,
b. a surfactant, and
c. a solubilizing agent
wherein, the pH of the solution ranges between 3.8-5.7, wherein the solution is stable for at least 6 months at 25 + 2°C / 60 + 5% RH. In another embodiment, the present invention provides a process for preparing an oral, aqueous solution comprising,
a. plurality of discrete units comprising cholecalciferol at a concentration in the range
of 400 IU-120000IU,
b. an aqueous vehicle,
wherein the process comprises step of dissolving the plurality of discrete units in an aqueous vehicle.
In another embodiment, the present invention provides a process for preparing an oral, aqueous solution comprising,
a. plurality of discrete units comprising cholecalciferol at a concentration in the range
of 400 IU-120000IU,
b. an aqueous vehicle, and

wherein the process comprises step of dissolving the discrete units in an aqueous vehicle
wherein, the discrete unit is in the form of pellets, granules, spheroids, particles, mini-tablets or beads.
In another embodiment, the present invention provides a process for preparing an oral, aqueous solution comprising,
a. pellets comprising cholecalciferol at a concentration in the range of 400 IU-120000
IU,
b. an aqueous vehicle, and
wherein the process comprises step of dissolving the discrete units in an aqueous vehicle.
In another embodiment, the present invention provides a process for preparing an oral, aqueous solution comprising,
a. plurality of discrete units comprising cholecalciferol at a concentration in the range
of 400 IU-120000 IU,
b. an aqueous vehicle, and
c. pharmaceutically acceptable excipients,
wherein the process comprises steps of dissolving the discrete units in an aqueous vehicle,
wherein, each discrete unit comprises an inert core and at least one coating layer.
In one aspect, at least one coating comprises water soluble polymer and pharmaceutically acceptable excipients.
In another aspect, at least one coating comprises cholecalciferol and pharmaceutically acceptable excipients.
In one aspect, each discrete units comprises an inert core and a drug coating layer surrounding the inert core.
In another aspect, the discrete units may additionally comprise a seal coating layer surrounding the inert core.
In another embodiment, the present invention provides a process for preparing an oral, aqueous solution comprising,
a. preparing plurality of discrete units comprising cholecalciferol,
b. dissolving the plurality of discrete units comprising cholecalciferol into an
aqueous vehicle.
Description of Embodiments
As used herein, the word "a" or "plurality" before a noun represents one or more of the particular nouns.

For the terms "for example" and "such as," and grammatical equivalences thereof, the phrase "and without limitation" is understood to follow unless explicitly stated otherwise.
The term "about," as used herein, refers to any value which lies within the range defined by a variation of up to +10% of the value.
As used herein, "drug," "active agent,", "pharmaceutically active agent," and "therapeutically active agent" may be used interchangeably to refer to an agent or substance that has measurable specified or selected physiological activity when administered to a subject in a significant or effective amount. These terms of art are well-known in the pharmaceutical and medicinal arts.
As used herein, the terms "formulation" and "composition" are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. When any of the above terms is modified by the term "oral" such terms refer to compositions, formulations, or dosage forms formulated and intended for oral administration to subjects.
As used herein, "pharmaceutically acceptable excipients" refers to a substance with which a drug may be combined to achieve a specific dosage formulation or oral dosage form for delivery to a subject.
The term "therapeutically effective amount" as used herein means that amount of cholecalciferol or its pharmaceutically acceptable salt that when administered to a mammal for treating a disease state, disorder or condition, is sufficient to effect such treatment. The therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal or human to be treated.
It should be noted that, as used herein the term "Vitamin D3" may be used interchangeably to refer to a cholecalciferol, a fat-soluble vitamin produced endogenously in human skin when 7-dehydrocholesterol is irradiated with UV light after sun exposure.
The term "oral administration" represents any method of administration in which an active agent can be administered by swallowing, chewing, or sucking or drinking an oral dosage form.
As used herein, the term "IU" refers to an abbreviation of "International Unit" measured as a quantity of a substance, such as a vitamin, hormone, or toxin, that produces a specified effect when tested according to an internationally accepted biological procedure.
The term "aqueous vehicle" used herein represents a water-contained vehicle that is capable of dissolving the plurality of discrete units. The aqueous vehicle would not

substantially affect the therapeutic effect of the active ingredients and would not cause undesired side effects on the treated subject.
The term "plurality of discrete units" used herein represents solid particles in the form of a pellet, granule, spheroid, particle, mini-tablet or bead. The term "granules", "pellets" or "spheroids" as used herein can be used interchangeably, and includes agglomeration from apparent solid powder particles to large multi-particulates. The agglomeration may be achieved by either granulation, compaction, extrusion, slugging, drug loading or the like. Such granules, pellets or spheroids have good flow property and these may be spherical or oval in shape, and may have a density higher than a powder. The granules or pellets or spheroids are coated, in particular, they can be preferably coated with at least one coating, as described herein.
The term "coating" as used herein the description, can be used interchangeably with the term "coat" or "layer" around the core.
The term "seal coating layer" used herein represents a polymer layer that surrounds a core. The term "drug coating layer" in the context of the present disclosure refers to a coating comprising "drug," "active agent,", "pharmaceutically active agent" or "therapeutically active agent" that surrounds a core.
The term "aqueous solution" means liquid composition containing water more than 50% by volume of the composition.
The term "overage," as used herein, refers to an additional quantity of cholecalciferol incorporated into the composition to ensure that 90% - 110% of the cholecalciferol content is maintained throughout the designated shelf life, to account for process loss or degradation, if any. The overage may be included in amounts of up to 100% based on the weight of cholecalciferol. Preferably, the overage may be included in amount up to 50%, and more preferably up to 25%, based on the weight of cholecalciferol. The present invention encompasses all such overages within these specified limits.
Unless otherwise defined, 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 invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
In one embodiment, the present invention provides an aqueous composition comprising, therapeutically effective amount of cholecalciferol and pharmaceutically acceptable excipients, wherein the composition is stable for at least 6 months, or 9 months, or 12 months or 24 months at 25 + 2°C / 60 + 5% RH.

In another embodiment, the present invention provides an aqueous composition comprising, therapeutically effective amount cholecalciferol and pharmaceutically acceptable excipients, wherein the composition is administered orally and wherein the composition is stable for at least 6 months, or 9 months, or 12 months or 24 months at 25 + 2°C / 60 + 5% RH.
In another embodiment, the present invention provides an oral, aqueous solution comprising, therapeutically effective amount cholecalciferol and pharmaceutically acceptable excipients, wherein the solution is stable for at least 6 months, or 9 months, or 12 months or 24 months at 25 + 2°C / 60 + 5% RH.
In another embodiment, the present invention provides an aqueous, oral solution comprising,
a. therapeutically effective amount of cholecalciferol,
b. a surfactant, and
c. a solubilizing agent.
In another embodiment, the present invention provides an aqueous, oral solution comprising,
a. therapeutically effective amount of cholecalciferol,
b. a surfactant,
c. a solubilizing agent, and
d. an antioxidant.
In another embodiment, the present invention provides an aqueous, oral solution comprising,
a. therapeutically effective amount of cholecalciferol,
b. a surfactant,
c. a solubilizing agent, and
d. an antioxidant,
wherein the solution is stable for at least 6 months at 25 + 2°C / 60 + 5% RH. In another embodiment, the present invention provides an aqueous, oral solution comprising,
a. cholecalciferol at a concentration in the range of 400 IU - 600000 IU, and
b. pharmaceutically acceptable excipients.
An oral, aqueous solution according to the present invention comprises cholecalciferol as a sole therapeutically active ingredient. It is present at a concentration ranging from about 400 IU to 600000 IU, such as for example, 400 IU, 600 IU, 800 IU, 1000 IU, 2000 IU, 3000 IU, 5000 IU, 10000 IU, 25000 IU, 50000 IU, 60000 IU, 100000 IU, 120000 IU, 300000 IU and 600000 IU. In one preferred embodiment, cholecalciferol is present at a concentration ranging from 54000 IU to 120000 IU. In another preferred embodiment, cholecalciferol is present at

a concentration of 60000 IU. In a further embodiment, appropriate amount of overage may be added in the compositions of the present invention to account for process loss or degradation, if any.
In another embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration of 54000 IU - 120000 IU and,
b. pharmaceutically acceptable excipients.
The aqueous solution of the present invention is clear in appearance, and oil-free. The aqueous solution of the present invention does not require an oil to dissolve a fat-soluble vitamin i.e., cholecalciferol.
The present invention relates to an oral solution wherein surfactants and solubilizing agents are incorporated in specific amounts to enhance the solubility of the drug. The selected excipients facilitate the maintenance of the drug in a solubilized state, ensuring uniform distribution throughout the formulation. This results in enhanced stability of the oral solution and enables consistent drug delivery. As a result, the formulation is well-suited for effective therapeutic administration.
The term "stable" as used herein, refers to the stability of cholecalciferol in an aqueous composition, wherein the aqueous composition looks clear on visual examination by naked eye when stored at or below 30°C for at least 6 months or 9 months, or 12 months or 24 months or longer. And also includes chemical stability which means the aqueous composition remains stable when stored:
- under the temperature and humidity conditions of 40°C /75%RH for at least 6 months, or 9 months, or 12 months, or 24 months or longer;
- under the temperature and humidity conditions of 30°C/ 65%RH for at least 6 months, or 9 months, or 12 months, or 24 months or longer;
- under the temperature and humidity conditions of 25 °C/ 60%RH for at least 6 months, or 9 months, or 12 months, or 24 months or longer.
In one embodiment, the present invention provides an oral, aqueous solution comprising,
a. cholecalciferol at a concentration of 54000 IU - 120000 IU,
b. a surfactant, and
c. a solubilizing agent.
In another embodiment, the present invention provides an aqueous, oral solution comprising,
a. cholecalciferol at a concentration of 54000 IU - 120000 IU,
b. a surfactant,
c. a solubilizing agent, and
d. an antioxidant.

In another embodiment, the present invention provides an aqueous, oral solution comprising,
a. cholecalciferol at a concentration of 54000 IU - 120000 IU,
b. a surfactant,
c. a solubilizing agent, and
d. an antioxidant,
wherein the solution is stable for at least 6 months at 25 + 2°C / 60 + 5% RH.
Surfactant used in the present invention are selected from polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
In one aspect, the surfactant includes, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl- 10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE- 10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl- 10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, a poloxamer, or a mixture thereof. In one preferred aspect, the surfactant is a poloxamer.
In on preferred aspect, the surfactant is selected from polyoxyethylene-polyoxypropylene block copolymers. In another preferred aspect, the polyoxyethylene-polyoxypropylene block copolymer is poloxamer.
In one aspect, an oral, aqueous solution of cholecalciferol comprises a surfactant in an amount of about 0.005 % w/v to 20 % w/v. In one preferred aspect, surfactant

is present in an amount ranging from 0.01% w/v to 5% w/v, such as for example, 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.25%, 3.5%, 3.75%, 4%, 4.25%, 4.5%, 4.75%, 5% w/v, or intermediates values thereof.
Solubilizing agents used in the present invention are selected polyethylene glycol (PEG) -derivatives of Vitamin E, for example, a vitamin E polyethylene glycol diester such as vitamin E sebacate polyethylene glycol, vitamin E dodecanedioate polyethylene glycol, vitamin E suberate polyethylene glycol, vitamin E azelaate polyethylene glycol, vitamin E citraconate polyethylene glycol, vitamin E methylcitraconate polyethylene glycol, vitamin E itaconate polyethylene glycol, vitamin E maleate polyethylene glycol, vitamin E glutarate polyethylene glycol, vitamin E glutaconate polyethylene glycol, vitamin E phthalate polyethylene glycol and vitamin E polyethylene glycol succinate (Tocophersolon). In one preferred aspect, the solubilizing agent is vitamin E polyethylene glycol succinate.
In one aspect, an oral, aqueous solution of cholecalciferol comprises a solubilizing agent in an amount of about 0.001% w/v to 10 % w/v. In one preferred aspect, surfactant is present in an amount ranging from 0.01% w/v to 3% w/v, such as for example, 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25%, 1.5%, 1.75%), 2%, 2.25%, 2.5%, 2.75%, 3% w/v, or intermediates values thereof.
The antioxidants used in the present invention are selected from butylhydroxytoluene (BHT), benzotriazol, butylhydroxyanisole (BHA), ascorbyl palmitate, disodium calcium ethylenediaminetetraacetate, DL-alpha- tocopherol, disodium ethylenediaminetetraacetate, erythorbic acid, dithiothreitol, monothioglycerol, thioglycerol, propyl gallate, erythorbate, sodium thioglycolate, thioglycerin, ascorbic acid, sodium sulfite, sodium bisulfite, sodium metabisulfite, cysteine, acetyl cysteine, histidine, glycine, and/or salts thereof and combinations thereof. In one preferred embodiment, the antioxidant is selected from butylated hydroxyanisole or butylated hydroxytoluene or mixture thereof.
In one aspect, an oral, aqueous solution of cholecalciferol comprises an antioxidant in an amount of about 0.001% w/v to 1 % w/v. In one preferred aspect, antioxidant is present in an amount ranging from, 0.001 %, 0.025 %, 0.050 %, 0.075 %, 0.1 %, 0.15 %, 0.2 %, 0.25 %, 0.3 %, 0.35 %, 0.4 %, 0.45 %, 0.5 %, 0.55 %, 0.6 %, 0.65 %, 0.7 %, 0.75 %, 0.8 %, 0.85 %, 0.9 %, 0.95 %, 1 % w/v, or intermediates values thereof.
In another aspect, an oral, aqueous solution of cholecalciferol further comprises a pH adjusting agent. The pH adjusting agent is selected from conjugate acid-base-pairs of organic acid or inorganic acids. The pH adjusting agents include but are not limited

to conjugate acid-base-pairs of organic acid selected from acetic acid, propionic acid, maleic acid, fumaric acid, malonic acid, malic acid, mandelic acid, citric acid, tartaric acid, succinic acid and mixture thereof. The pH adjusting agents include but are not limited to conjugate acid-base-pairs of inorganic acid selected from hydrochloric acid, phosphoric acid, boric acid and mixture thereof. In one preferred aspect the pH adjusting agent is conjugate acid-base pair of citric acid.
In one aspect, an oral, aqueous solution of cholecalciferol comprises a pH adjusting agent in an amount of about 0.001% - 1 % w/v. In one preferred embodiment the concentration of the pH adjusting agent in an aqueous solution is in the range of about 0.005 % w/v - 0.5 % w/v.
The aqueous solution according to the present invention has a pH in the range of about 3.8 to 5.7; for example, 3.8, 3.9, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6 or 5.7 or intermediate values thereof. In one preferred embodiment the pH is in the range of about 4.5 to 5.5. In another preferred embodiment the pH of the aqueous solution is 4.7 + 0.2.
In another aspect, an oral, aqueous solution of cholecalciferol further comprises a preservative. The preservative includes but are not limited to phenol, metacresol, benzyl alcohol, methaform, ethyl alcohol, Phenoxyethanol, methyl hydroxybenzoate, nipasol, benzalkonium chloride, thimerosal, methyl paraben, propyl paraben, sorbic acid or its potassium salt and combination thereof. The concentration of a preservative in an aqueous solution is in the range of about 0.005% w/v - 2 % w/v. In one preferred embodiment the concentration of a preservative in an aqueous solution is in the range of about 0.05% w/v - 0.5 % w/v.
In another aspect, an oral, aqueous solution of cholecalciferol further comprises a sweetener. The sweetener includes but are not limited to cyclamate, saccharin, sodium saccharin, aspartame, sucralose, neotame, thaumatin, neohesperidine, acesulphame potassium, acesulphame-aspartame salt, sorbitol, and combination thereof. The concentration of a sweetener in an aqueous solution is in the range of about 0.001% w/ v - 1 % w/v. In one preferred embodiment the concentration of the preservative in the aqueous solution is in the range of about 0.02 % w/v - 0.4 % w/v.
In another aspect, an oral, aqueous solution of cholecalciferol further comprises a colorant. The colorant may be selected from water-soluble synthetic organic food additives, water-insoluble lake dyes, natural pigments and combination thereof. The concentration of a colorant in an aqueous solution is in the range of about 0.0001% w/ v - 0.01 % w/v.
In another aspect, an oral, aqueous solution of cholecalciferol may further include a flavoring agent to enhance palatability or mask undesirable taste. The flavoring agents may be selected from the group consisting of natural flavoring agents, artificial

flavoring agents, sweetening agents, aromatic compounds, acidulants, either alone or in combination thereof. In one aspect, a flavoring agent is present in the range of about 0.002 % w/v - 2 % w/v.
In another embodiment, the present invention provides a process for preparing an oral, aqueous solution comprising,
a. plurality of discrete units comprising cholecalciferol at a concentration in
the range of 400 IU-120000 IU,
b. b. an aqueous vehicle,
wherein the process comprises step of dissolving the plurality of discrete units in an aqueous vehicle.
In one aspect, the plurality of discrete units comprising cholecalciferol is in the form of pellets, granules, spheroids, particles, mini-tablets or beads. In another aspect, the plurality of discrete units comprising cholecalciferol is in the form of pellet or particle. In one preferred aspect, the plurality of discrete units comprising cholecalciferol is in the form of a pellet.
In another aspect, each discrete unit comprises cholecalciferol and pharmaceutically acceptable excipients. In one aspect, each discrete unit comprises, an inert core and at least one coating comprising water soluble polymers and pharmaceutically acceptable excipients. In another aspect, at least one coating of each discrete unit comprises cholecalciferol and pharmaceutically acceptable excipients.
In another aspect, each discrete unit comprises an inert core and a drug coating layer surrounding the inert core. In one aspect, the discrete units may additionally comprise a seal coating layer surrounding the inert core.
The inert core of present invention may be a sphere or bead of sugar, a hydrophilic cellulosic polymer, or a crosslinked hydrophilic synthetic polymer. In one preferred aspect, the inert core of present invention is sphere or bead of sugar.
The plurality of discrete units comprising cholecalciferol are prepared by, applying a drug coating layer to an inert core. Optionally, the plurality of discrete units comprising cholecalciferol are prepared by, applying a seal coating layer between the inert core and drug coating layer.
In another aspect, the plurality of discrete units comprising cholecalciferol are prepared by applying the seal coating layer to the inert core, further applying drug coating layer to the seal coated units.
In one aspect, the drug coating layer surrounding an inert core comprises cholecalciferol and pharmaceutically acceptable excipients. In one aspect, the drug coating layer comprises about 5% w/w -45% w/w of the discrete unit. In one preferred aspect, the drug coating layer comprises about 10% w/w - 30% w/w of the discrete unit. The drug coating layer comprises about 0.1% w/w - 30% w/w of the drug based

on the weight of the drug coating layer. In one preferred aspect, the drug coating layer comprises about 0.5% w/w - 15% w/w of the drug based on the weight of the drug coating layer.
The drug coating layer comprises a water-soluble polymer in a concentration of at least 30% w/w based on the weight of the drug coating layer. In one preferred aspect, the drug coating layer comprises a water-soluble polymer in a concentration of at least 50% w/w based on the weight of the drug coating layer.
The drug coating layer of the present invention further comprise a solubilizing agent in an amount of about 0.05% to 25% w/w based on weight of the drug coating layer. In one preferred aspect, the drug coating layer comprises solubilizing agent in an amount of about 0.1% w/w - 10% w/w based on weight of the drug coating layer.
The drug coating layer of the present invention comprises a surfactant in an amount of about 0.3 w/w % to 35 % w/w based on weight of the drug coating layers. In one preferred aspect, the drug coating layer comprises surfactant in an amount of about 0.5% w/v to 25 % w/v.
The drug coating layer of the present invention further comprises antioxidants in an amount of about 0.01 w/w % to 10% w/w based on weight of the drug coating layer. In one preferred aspect, the drug coating layer comprises antioxidants in an amount of about
In another aspect, the seal coating layer comprises about 0.1% w/w - 20% w/w of the discrete unit. In one preferred aspect the seal coating layer comprises about 1% w/w -10% w/w of the discrete unit. In another aspect, the seal coating layer comprises water soluble polymer in a concentration of at least 70% w/w based on the weight of the seal coating layer. In one preferred aspect, the seal coating layer comprises water soluble polymer in a concentration of at least 95% w/w based on the weight of the seal coating layer.
Coating may be carried out by using any conventional coating techniques known in the art, such as, spray coating in a conventional coating pan, fluidized bed processor, or dry powder coating, or a combination thereof.
The plurality of discrete units further may comprise other pharmaceutically accepted excipients. The pharmaceutically acceptable excipients include but are not limited to stabilizers, binders, diluents, disintegrants, pore- formers, lubricants/glidants and combination thereof.
In another embodiment, the process for preparing an oral, aqueous solution comprises, preparing plurality of discrete units comprising cholecalciferol and dissolving the plurality of discrete units comprising cholecalciferol into an aqueous vehicle.

The plurality of discrete units comprising cholecalciferol are prepared by various methods including fluidized bed granulation, wet granulation, solvent evaporation, spray drying, or a combination thereof.
In another embodiment, the present invention provides a process for preparing an oral, aqueous solution comprising,
a. plurality of discrete units comprising cholecalciferol
b. an aqueous vehicle and,
wherein the process comprises steps of dissolving the plurality of discrete units in an aqueous vehicle.
The aqueous vehicle comprises pharmaceutically acceptable excipients, for example, pH adjusting agents, preservative, stabilizers, antioxidants, sweetener, flavoring agent, colorant, and mixture thereof.
The following non-limiting examples illustrate the scope of the present disclosure without any limitation thereto. It is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms.
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Example 1: Cholecalciferol solution comprising two coating layer pellets
Table: 1 Cholecalciferol oral Solution 60000 IU/5 ml

Composition I II Ill IV
Sr. No. Ingredients Quantity (mg/5 ml)
Starting material
1 Sucrose 333.325 333.325 333.325 333.325
Stage A: Seal coating
2 Hypromellose (E5,
AN 5) 16.500 16.500 - -
3 Hypromellose (E3) - - 16.500 -
4 Hydroxy Propyl Ce llulose - - - 16.500

5 Butylated Hydroxy toluene 0.175 0.175 0.175 0.175
6 Isopropyl Alcohol q.s. q.s. q.s. q.s.
7 Dichloromethane q.s. q.s. q.s. q.s.
Stage B: Drug layering
8 Seal coated pellets 350.000 350.000 350.000 350.000
9 Cholecalciferol [60 000 IU + 25 % ove rages] 1.875 1.875 1.875 1.875
10 Vitamin E polyeth ylene glycol succin ate 5.000 5.000 5.000 5.000
11 Poloxamer 12.500 5.000 5.000 5.000
12 Hypromellose (E5,
AN 5) 37.100 37.100 - -
13 Hypromellose (E3) - - 37.100 -
14 Hydroxy Propyl Ce llulose - - - 37.100
15 Sorbic Acid 0.263 0.263 0.263 0.263
16 Butylated Hydroxy toluene 0.262 0.262 0.262 0.262
17 Butylated Hydroxy anisole 0.500 0.500 0.500 0.500
18 Isopropyl Alcohol q.s. q.s. q.s. q.s.
19 Dichloromethane q.s. q.s. q.s. q.s.
Stage C: Solution preparation
20 Vitamin D3 Pellets 407.500 400.000 400.000 400.000
21 Sodium Benzoate 10.000 10.000 10.000 10.000
22 Sodium Citrate 15.000 15.000 15.000 15.000
23 Citric Acid Monoh ydrate 10.000 10.000 10.000 10.000
24 Sucralose 8.000 8.000 8.000 8.000

25 Vanilla Flavor 3.000 3.000 3.000 3.000
26 Honey Flavor 3.000 3.000 3.000 3.000
27 Peppermint Flavor 1.500 1.500 1.500 1.500
28 Tartrazine Supra 0.080 0.080 0.080 0.080
29 Purified Water q.s. to 5 ml q.s. to 5 ml q.s. to 5 ml q.s. to 5 ml
Table: 2 Cholecalciferol oral solution 400 IU/0.5 ml

Composition V
Sr.N
0. Ingredients Quantity (ug/0.5 ml)
Starting Material
1 Sucrose (Sugar Globules 30#-40#) 222.217
Stage A: Seal Coating
2 Hypromellose (E5/AN 5) 11.000
3 Butylated Hydroxy toluene 0. 117
4 Isopropyl Alcohol q.s.
5 Dichloromethane q.s.
Net Weight of Seal Coated Pellets 233.333
Stage B: Drug Layering
6 Seal Coated Pellets 233.333
7 Cholecalciferol [60000 IU + 25 % overages] 1.250
8 Vitamin E Polyethylene Glycol Succinate 3.333
9 Poloxamer (188) (Kolliphor P 188 Micro) 8.333
10 Hypromellose (E5/AN 5) 24.733
11 Sorbic Acid 0.175
12 Butylated Hydroxy toluene 0.175
Butylated Hydroxyanisole 0.333
13 Isopropyl Alcohol q.s.
14 Dichloromethane q.s.
Net Weight of Drug Layered Pellets 271.667
Stage C: Solution Preparation

15 Cholecalciferol Pellets 271.667
16 Sodium Benzoate 1000.000
17 Sodium Citrate 1500.000
18 Citric Acid Monohydrate 1000.000
19 Sucralose 800.000
20 Vanilla Flavor 300.000
21 Honey Flavor 300.000
22 Peppermint Flavor 150.000
23 Tartrazine Supra 8.000
24 Purified Water q.s. to 0.5 ml
Manufacturing Process for composition I - V:
Stage A: Seal Coating
The required quantities of Hypromellose or hydroxypropyl cellulose were added in the isopropyl alcohol under continuous stirring. Further, dichloromethane and butylated hydroxytoluene were added under continuous stirring until a clear solution formed.
The fluid bed processor was prepared for coating process, sucrose globules were added in the product container and 25 - 35°C temperature was maintained.
The seal coating solution prepared earlier was sprayed on the pre-warmed sucrose globules.
The seal coating layer pellets were dried and LOD was measured. [Limit: NMT 2.0%w/w].
The seal coating layer pellets were sifted through ASTM 24# and 40#. Oversize of 24# and undersize of 40# were discarded.
Stage B: Drug Layering
The half of the total quantity of Hypromellose and isopropyl alcohol were mixed with continuous stirring. Further, half of the total quantity of dichloromethane was added with continuous stirring until a clear solution formed.
In a different container the remaining quantity of isopropyl alcohol and dichloromethane were mixed. In this solution, butylated hydroxytoluene, butylated hydroxyanisole, sorbic acid and Vitamin E Polyethylene Glycol Succinate were added following the addition of poloxamer. This mixture was stirred until a clear solution formed.

The two above-mentioned solutions were mixed with continuous stirring. In this mixture solution, cholecalciferol was added and stirred until a clear drug coating solution formed.
The fluid bed processor was prepared for coating process, seal coating layer pellets were loaded for the drug layer coating process.
The drug coating layer solution was sprayed onto the seal coating layer pellets to form drug coating layer pellets/ vitamin D3 pellets.
The drug coating layer pellets were dried and LOD was measured. [Limit: NMT 2.0%w/w].
The dried drug coating layer pellets were sifted through ASTM 20# and ASTM 40#. The oversize and undersize pellets were discarded.
Stage C: Solution Preparation
In a vessel, approximately 80% of the total quantity of the purified water was stirred continuously.
The Vitamin D3 pellets were added directly into the vortex of above purified water with continuous stirring. The other remaining excipients were added directly into the vortex of above solution with continuous stirring.
The volume was made up with the remaining quantity of purified water, solution was filtered through cartridge filter or through muslin cloth or through 200# ASTM sieve.
Example 2: Cholecalciferol solution comprising one coating layer pellets
Table: 3 Cholecalciferol oral solution 60000 IU/5 ml

Composition VI
Sr. No. Ingredients Quantity (mg/5 ml)
Starting Material
1 Sucrose 333.325
Stage A: Drug coating layer preparation
2 Cholecalciferol [60000 IU + 25 % overages of Vitamin D3] 1.875
3 Vitamin E Polyethylene Glycol Succinate 5.000
4 Poloxamer (188) (Kolliphor P 188 Micro) 12.500
5 Hypromellose (E5/AN 5) 53.600
6 Sorbic Acid 0.263
7 Butylated Hydroxy toluene 0.437
8 Butylated Hydroxyanisole 0.500
9 Isopropyl Alcohol q.s.

10 Dichloromethane q.s.
Stage B: Solution preparation
11 Cholecalciferol Granules 407.500
12 Sodium Benzoate 10.000
13 Sodium Citrate 15.000
14 Citric Acid Monohydrate 10.000
15 Sucralose 8.000
16 Vanilla Flavor 3.000
17 Honey Flavor 3.000
18 Peppermint Flavor 1.500
19 Tartrazine Supra 0.080
20 Purified Water q.s. to 5 ml
Manufacturing Process for composition VI:
Stage A: Drug coating layer preparation
The half of the total quantity of isopropyl alcohol and Hypromellose were mixed under continuous stirring. Further, the half of the total quantity of dichloromethane was added and stirred until a clear solution formed.
In a different vessel the other half of the total quantity of isopropyl alcohol and dichloromethane were mixed to form a vortex. In this mixture, butylated hydroxytoluene, butylated hydroxyanisole and sorbic acid were added to form a clear solution. Further, Vitamin E Polyethylene Glycol Succinate and poloxamer were added and stirred until a clear solution formed.
The two above-mentioned solutions were mixed under continuous stirring. In this mixture solution, cholecalciferol was dissolved until a clear drug coating solution formed.
The fluid bed processor was prepared for coating process, sucrose globules were loaded for the drug layer coating process.
The drug coating layer solution was sprayed onto the sucrose globules to form drug coating layer pellets/ vitamin D3 pellets.
The drug coating layer pellets were dried and LOD was measured. [Limit: NMT 2.0%w/w].
The dried granules were sifted through ASTM 16# and the oversized pellets were discarded.
Stage B: Solution Preparation with Stirring

In a vessel, approximately 80% of the total quantity of the purified water was stirred continuously.
The Vitamin D3 pellets were added directly into the vortex of above purified water with continuous stirring. The other remaining excipients were added directly into the vortex of above solution with continuous stirring.
The volume was made up with the remaining quantity of purified water, solution was filtered through cartridge filter or through muslin cloth or through 200# ASTM sieve.
Example 3: Cholecalciferol solution comprising cholecalciferol powder
Table: 4 Cholecalciferol oral solution 60000 IU/5 ml

Prototype VII VIII IX
Sr.N
0. Ingredients Quantity ( mg/5 ml)
Stage A: Spray Drying
1 Cholecalciferol [60000 IU + 25 % overages of Vitamin D3] 1.875 1.875 1.875
2 Vitamin E Polyethylene Glycol Succinate 5.000 5.000 5.000
3 Poloxamer (188) (Kolliphor P 188 Micro) 5.000 5.000 37.500
4 Hypromellose (E5/AN 5) 37.100 37.100 37.100
5 Sorbic Acid 0.263 0.263 0.263
6 Butylated Hydroxy toluene 0.262 0.262 0.262
7 Butylated Hydroxyanisole 0.500 0.500 0.500
8 Isopropyl Alcohol q.s. q.s. q.s.
9 Dichloromethane q.s. q.s. q.s.
Net Weight of Spray Dried Powder 50.000 50.000 82.500
Stage B: Solution Preparation
10 Cholecalciferol dry Powder 50.000 50.000 82.500
11 Sucrose 266.66 - -
12 Sodium Benzoate 10.000 10.000 10.000
13 Sodium Citrate 15.000 15.000 15.000
14 Citric Acid Monohydrate 10.000 10.000 10.000
15 Sucralose 8.000 8.000 8.000
16 Vanilla Flavor 3.000 3.000 3.000

17
Honey Flavor 3.000 3.000 3.000
18 Peppermint Flavor 1.500 1.500 1.500
19 Tartrazine Supra 0.080 0.080 0.080
20 Purified Water q.s. to 5 m 1 q.s. to 5 m 1 q.s. to 5 ml
Manufacturing Process- composition VII - IX
Stage A: Spray Drying
The Hypromellose was disperse in the half of the total quantity of isopropyl alcohol and the half of the total quantity of dichloromethane under continuous stirring.
In a different vessel, the remaining quantity of isopropyl alcohol and dichloromethane were mixed with continuous stirring to form a vortex. In this mixture, butylated hydroxytoluene, butylated hydroxyanisole, sorbic acid, Vitamin E Polyethylene Glycol Succinate and poloxamer were added. The solution was stirred until a clear solution formed.
The two above-mentioned solutions were mixed under continuous stirring. In this mixture solution, cholecalciferol was dissolved until a clear drug coating solution formed.
The abovementioned solution was spray dried to obtain a cholecalciferol powder.
Stage B: Solution Preparation
In a vessel, approximately 80% of the total quantity of the purified water was stirred continuously.
The Vitamin D3 powder was added directly into the vortex of above purified water with continuous stirring. The other remaining excipients were added directly into the vortex of above solution with continuous stirring.
The volume was made up with the remaining quantity of purified water, solution was filtered through cartridge filter or through muslin cloth or through 200# ASTM sieve.
Example 4: Testing of Physical and Chemical Stability
The oral composition of Example 1 was checked for chemical stability upon storage at room temperature (25°C/60% relative humidity) at 30°C/75% relative humidity and at 40°C/75% relative humidity (accelerated storage stability condition). The assay of Vitamin D3 (% of label claim) and pH upon storage were determined at different time points and are tabulated below in Table 5:
Table 5: Stability study results for oral composition of example 1:

Sr Parameter 0M 25°C/60% RH 30°C/75% RH 40°C/75% RH

1M 3M 6M 1M 3M 6M 1M 3M 6M

1 Assay of V itamin D3 ( %)* NLT 90% 129.78 130.4 129.51 126.14 129.89 130.71 122.57 127.99 127.6 109.25
2 PH Between 3.
8-5.7 4.74 4.77 4.80 4.83 4.77 4.79 4.82 4.74 4.79 4.80
*Any value beyond 125% indicates overages added
The above data shows that the assay of Vitamin D3 was within the require limit upon storage. Thus, it can be concluded that the oral composition of Example 1 was found to be chemically stable when stored at room temperature (25°C/60% relative humidity) for 6 months and at 40°C/75% relative humidity (accelerated storage stability condition) for a prolonged period of at least 6 months.

Claims
[Claim 1] An aqueous, oral solution comprising,
a. therapeutically effective amount of cholecalciferol,
b. a surfactant in an amount of about 0.01% w/v to 5 % w/v,
and
c. a solubilizing agent in an amount of 0.01% w/v to 3 % w/
v.
[Claim 2] The solution as claimed in claim 1, wherein the solution
comprises cholecalciferol at a concentration of 400 IU - 120000 IU.
[Claim 3] The solution as claimed in claim 1, wherein the solution
comprises cholecalciferol at a concentration of 60000 IU.
[Claim 4] The solution as claimed in claim 1, wherein the surfactant is
selected from the group consisting of polyoxyethylene alkyl ethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
[Claim 5] The solution as claimed in claim 4, wherein the surfactant is a
polyoxyethylene-polyoxypropylene block copolymers.
[Claim 6] The solution as claimed in claim 1, wherein the solubilizing agent
is polyethylene glycol derivatives of vitamin E.
[Claim 7] The solution as claimed in claims 1-6, wherein the solution further
comprises an antioxidant.
[Claim 8] The solution as claimed in claim 7, wherein the antioxidant is
selected from the group consisting of ascorbic acid, tocopherol, butylated hydroxyanisole, propyl gallate, sodium sulfite, sodium bisulfite, sodium metabisulfite, cysteine, acetyl cysteine, histidine, glycine, arginine or mixture thereof.
[Claim 9] The solution as claimed in claim 8, wherein the antioxidant is in
an amount of about 0.001% w/v to 1 % w/v.

[Claim 10] The solution as claimed in claim 9, wherein the solution has a pH
of 3.8-5.7.
[Claim 11] The solution as claimed in claim 1-10, wherein the solution is
prepared by dissolving a plurality of discrete units comprising cholecalciferol in an aqueous vehicle.
[Claim 12] The solution as claimed in claim 11, wherein the discrete unit
comprising cholecalciferol is in the form of a pellet.
[Claim 13] The solution as claimed in claim 12, wherein the discrete unit
comprises, an inert core, seal coating layer and drug coating layer.
[Claim 14] The solution as claimed in claim 13, wherein the discrete unit
comprising cholecalciferol is prepared by, i. applying a seal coating layer to an inert core, ii. applying a drug coating layer to a seal coated core.
[Claim 15] The solution as claimed in claim 14, wherein the inert core is
selected from the group consisting bead of sugar, a hydrophilic cellulosic polymer, or a crosslinked hydrophilic synthetic polymer.
[Claim 16] The solution as claimed in claim 15, wherein the seal coating
layer comprises water-soluble polymers and pharmaceutically acceptable excipients thereof.
[Claim 17] The solution as claimed in claim 13, wherein the drug coating
layer comprises cholecalciferol, water-soluble polymers and pharmaceutically acceptable excipients thereof.
[Claim 18] The solution as claimed in claims 16-17, wherein the water-
soluble polymer is selected from the group consisting of ethyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and mixtures thereof.
[Claim 19] An aqueous, oral solution comprising,
Cholecalciferol at a concentration of 54000 IU - 120000 IU,
a surfactant in an amount of about 0.01% w/v to 5 % w/v,
a solubilizing agent in an amount of about 0.01% w/v to 3 % w/v,
and
an antioxidant in an amount of about 0.001% w/v to 1% w/v.
[Claim 20] The solution as claimed in claim 18, wherein the surfactant is
poloxamer.
[Claim 21] The solution as claimed in claim 18, wherein the solubilizing
agent is vitamin E polyethylene glycol succinate.

[Claim 22] The solution as claimed in claim 18, wherein the antioxidant is
butylated hydroxyanisole or butylated hydroxytoluene or mixture thereof.
[Claim 23] The solution as claimed in claims 1-21, wherein, the solution is
stable for at least 6 months at 25 + 2°C / 60 + 5% RH.