Claims:CLAIMS
I/We Claim,
1. An orally disintegrable pharmaceutical composition for rapid release and increased bioavailability of a drug comprising:
a cholecalciferol (410) that acts as an active ingredient of the drug;
a propylene glycol (430) to stabilize the active ingredient;
a polyethylene glycol (PEG) (420) as an excipient of the drug; and
a mannitol (440) to provide a matrix for encapsulating the active ingredient, stabilizer and the drug excipient, wherein the cholecalciferol is dispersed as nano-particles of size 300 nm within the matrix and gets released by rapid dissolution of the PEG and the mannitol when administered orally.
2. The orally disintegrable pharmaceutical composition as claimed in claim 1, wherein the mannitol is blended with a flavouring agent (450) optionally to provide a flavour to the composition for oral administration.
3. The orally disintegrable pharmaceutical composition as claimed in claim 2, wherein the composition for a single dosage form of 500 mg comprises at least 50 mcg of the cholecalciferol, 0.006 mg of the propylene glycol, 25 mg of the PEG, 454.994 mg of the mannitol and 20 mg of the flavouring agent.
4. The orally disintegrable pharmaceutical composition as claimed in claim 3, wherein the bioavailability of the cholecalciferol is 90-95% when administered orally.
5. A method of preparing an orally dispersible pharmaceutical composition for cholecalciferol comprising:
taking cholecalciferol (310) as an active ingredient;
adding propylene glycol (320) as a stabilizing agent;
adding molten form of polyethylene glycol (PEG) (330) as an excipient;
ultrasonicating the mixture (340) and crushing it before condensation to obtain a plurality of nanoparticles of cholecalciferol; and
adding mannitol (350) to form a primary matrix for encapsulating the cholecalciferol, wherein the plurality of nanoparticles of the cholecalciferol are of size 300 nm and are dispersed uniformly within the primary matrix.
6. The method as claimed in claim 5, wherein the ultrasonication is performed at an ultrasonic frequency of 50000 watts for at least 120 seconds.
7. The method as claimed in claim 6, wherein the primary matrix and the PEG gets dissolved rapidly when they get in contact with a body fluid thereby releasing the cholecalciferol exhibiting increased bioavailability inside a human body.
8. A method, system and apparatus providing one or more features as described in the paragraphs of this specification.

Date: 27-03-2019 Signature…………………………
, Description:Form 2
The Patent Act 1970
(39 of 1970)
AND
Patent Rules 2003
Complete Specification
(Sec 10 and Rule 13)

Title A Method and Orally Disintegrable Pharmaceutical Composition for Cholecalciferol
Applicant(s) Stabicon Life Sciences Pvt Ltd
Nationality India
Address #28, Bommasandra Industrial Area (Sub Layout), 4th Phase, Jigani Hobli, Anekal Taluk, Bengaluru – 560100, Karnataka, India

The following specification, particularly describes the invention and the manner in which it is to be performed.

DESCRIPTION
FIELD OF INVENTION
[0001] Embodiments of the present disclosure relate generally to an oral pharmaceutical composition and more specifically to a method and orally dispersible/disintegrable pharmaceutical composition prepared by using vitamin D nanoparticles.
RELATED ART
[0002] Cholecalciferol (Vitamin D3) is a naturally synthesized vitamin in skin which plays a vital role in maintaining calcium levels in blood and promoting bone health and development. Individuals with lower blood levels due to lack of sun exposure, the obese, and darker skinned individuals with low levels of phosphate in the blood are required to rely on external intake of cholecalciferol. Conventionally, cholecalciferol is provided orally as a dietary supplement or by intramuscular injections for treating vitamin D deficiency.
[0003] Conventional oral supplements of cholecalciferol in solid forms are having less bioavailability as the cholecalciferol is provided in combination of other active and pharmaceutically acceptable excipients for example, calcium and the like. In conventional solid formulations, the cholecalciferol gets completely adsorbed within a matrix formed by a combination of conventional polymers and other components. However, the entire adsorbed cholecalciferol is not desorbed when administered orally and results in regular intakes throughout the day to meet the recommended intake of the cholecalciferol.
[0004] Consumption of the cholecalciferol in liquid dosage form for example, drops and syrup are not comfortable to an individual which may leads to dosage noncompliance. Further, liquid dosages are economically unfeasible for transportation, breakages and handling of large volumes. Also, the liquid dosage forms require preservatives, solubilizing agents in addition to the pharmaceutically acceptable excipients and other components.
[0005] Thus, it is necessary to provide an orally dispersible solid form of a pharmaceutical composition with increased bioavailability of the cholecalciferol without the need of preservatives.
SUMMARY
[0006] According to an aspect of the present disclosure, an orally dispersible/disintegrable pharmaceutical composition for rapid release and increased bioavailability of a drug comprising a cholecalciferol (410) that acts as an active ingredient of the drug, a propylene glycol (430) to stabilize the active ingredient, a polyethylene glycol (PEG) (420) as an excipient of the drug, and a mannitol (440) to provide a matrix for encapsulating the active ingredient, stabilizer and the drug excipient, wherein the cholecalciferol is dispersed as nanoparticles of size 300 nm within the matrix and gets released by rapid dissolution of the PEG and the mannitol when administered orally. In an embodiment, the mannitol is blended with a flavouring agent (450) and the pharmaceutical composition for a single dosage form of 500 mg comprises at least 400 iu to 60,000 iu of the cholecalciferol, 0.006 mg of the propylene glycol, 25 mg of the PEG, 454.994 mg of the mannitol and 20 mg of the flavouring agent.
[0007] Several aspects are described below, with reference to diagrams. It should be understood that numerous specific details, relationships, and methods are set forth to provide full understanding of the present disclosure. Skilled personnel in the relevant art, however, will readily recognize that the present disclosure can be practiced without one or more of the specific details, or with other methods, etc. In other instances, well-known structures or operations are not shown in detail to avoid obscuring the features of the present disclosure.
BRIEF DESCRIPTION OF DRAWINGS
[0008] FIG. 1 is a diagram illustrating the commercial production of cholecalciferol in an example.
[0009] FIG. 2A and 2B are the diagrams illustrating phases of a solid drug absorption and the less bioavailability of cholecalciferol in an example.
[0010] FIG. 3 is a flowchart illustrating the steps involved in preparing the orally dispersible/disintegrable pharmaceutical composition with nano-particles of the cholecalciferol in an embodiment of the present disclosure.
[0011] FIG. 4 is a table illustrating an optimum composition for preparing the orally dispersible/disintegrable sachets and/or pouches of cholecalciferol in an embodiment of the present disclosure.
[0012] FIG. 5 is a table illustrating an optimum composition for preparing the orally dispersible/disintegrable tablets of cholecalciferol in an embodiment of the present disclosure.
[0013] FIG. 6A and 6B are the schematic drawings illustrating the disintegration of the cholecalciferol in oral cavity by administering the tablets and sachets/pouches of the present disclosure.
DETAILED DESCRIPTION OF THE PREFERRED EXAMPLES
[0014] FIG. 1 is a diagram illustrating the commercial production of cholecalciferol in an example. Cholecalciferol is a form of Vitamin D produced within the body or obtained from sun light with one ring open as shown in the figure. Cholecalciferol is also produced industrially for using as a vitamin supplement and for enrichment of food products. Commercially production of the cholecalciferol comprises the production of 7-dehydrocholesterol (110) from lanolin found as cholesterol component in sheep wool, irradiating the 7-dehydrocholesterol with ultraviolet rays (140) and removing undesired isomers (120) synthesized during irradiation. The cholesterol is extracted from a wool grease and wool wax alcohols obtained from cleaning of the wool after shearing. As shown there, the 7-dehydrocholesterol (110) is irradiated with ultraviolet light (140) for a predetermined period of time to produce cholecalciferol (130) along with isomers (120).
[0015] In a human body, 7-dehydrocholesterol which acts as a precursor of cholecalciferol undergoes an electrocyclic reaction within the epidermal layer of skin when exposed to UV light at wavelengths of range 290-315 nm through the sunlight. This results in opening of the vitamin precursor B-ring and isomerizes to form the cholecalciferol.
[0016] Cholecalciferol helps kidneys to recycle phosphate back into the blood stream to maintain a healthy pH and also increases the uptake of calcium by intestines. Thus, it helps in increasing the bone mass in adults as well as in treating rickets in children. However, the production of cholecalciferol is deficient in individuals with no proper exposure to sunlight and due to heredity. In order to provide recommended dosage of cholecalciferol to hum body, there are various types of dosage forms such as solids and liquids. However, conventional dosage forms are having less bioavailability inside the human body due to practically insoluble nature of cholecalciferol in the water. Hence, an orally dispersible/disintegrable pharmaceutical composition is provided in the present disclosure.
[0017] FIG. 2A and 2B are the diagrams illustrating phases of a solid drug absorption and the less bioavailability of cholecalciferol in an example. As shown in the FIG. 2A, 201 represents a disintegration phase while 203 represents a dissolution phase of the cholecalciferol in an example. In the disintegration phase (201), a solid drug dosage (202) form comprising cholecalciferol as an active ingredient is administered orally to an individual. Once the drug is administered into the body, a plurality of granules (204) comprising the cholecalciferol and other active and inactive components of the solid dosage gets released into the blood stream. Further, the cholecalciferol (206) present in the solid drug dosage (202) gets separated and enters into the dissolution phase (203). In dissolution phase (203), the fine particles of cholecalciferol (206) enters into the gastro-intestinal (GI) tract (208) where the active components in the solid drug dosage form are absorbed. The absorbed active components such as cholecalciferol then flows through the blood stream and reaches a target site (210) where its action is required to be performed. However, the bioavailability of the cholecalciferol is very low due to the insoluble nature of cholecalciferol in water and less desorption into the GI tract (208) from the solid dosage form (202). FIG. 2B illustrates the poor bioavailability of the cholecalciferol (206) in GI tract using conventional solid drug dosage forms (202). As shown in the FIG. 2B, the cholecalciferol (206) enters into the stomach (212) wherein a very less amount of cholecalciferol particles enters the intestine (214) before reaches the target site (210) while the maximum amount of the cholecalciferol gets excreted from the body. As the administered cholecalciferol from a single drug dosage form is not utilized completely by the body, intake of the solid drug dosage forms (202) gets increased which may leads to harmful side effects. Thus, an orally dispersible/disintegrable pharmaceutical composition for administering cholecalciferol into the body by increasing its bioavailability and dispersion is provided in the present disclosure.
[0018] FIG. 3 is a flowchart illustrating the steps involved in preparing the orally dispersible/disintegrable pharmaceutical composition with nano-particles of the cholecalciferol in an embodiment of the present disclosure. As shown there, the method (300) of preparing an orally dispersible pharmaceutical composition starts with step 310. In step 310, a substantial amount of the cholecalciferol produced by industrial process is used as an active ingredient. In an embodiment, 50 mcg (appx) of the cholecalciferol which is prepared by conventional industrial process is collected and used for the preparing the orally dispersible/disintegrable pharmaceutical composition of the present disclosure.
[0019] In step 320, propylene glycol is added to the cholecalciferol as a stabilizing agent and preservative and mixed by using conventional mechanism to obtain a homogenous powder. In an embodiment, at least 0.006 mg of the propylene glycol is added to 50 mcg (appx) of the cholecalciferol.
[0020] In step 330, a molten form of polyethylene glycol (PEG) is added to the homogenous powder of the cholecalciferol and the propylene glycol. The PEG acts as a pharmaceutical excipient in preparing the orally dispersible pharmaceutical composition of the present disclosure. In an embodiment, at least 25 mg of PEG is used for preparing a homogenous mixture of the cholecalciferol, propylene glycol and the PEG.
[0021] In step 340, the homogenous mixture is ultrasonicated using the ultrasonic frequencies of 50000 watts for a predetermined period of at least 120 seconds alternatively at regular intervals of 10 seconds and 30 seconds respectively. The sonication of the mixture results in dispersion of the cholecalciferol in molten polyethylene glycol. The resulting mixture after sonication is then condensed and crushed to form nanoparticles of the cholecalciferol.
[0022] In step 350, mannitol is added as a sugar alcohol which acts as a primary matrix to form a blend of encapsulated nanoparticles of cholecalciferol. In an embodiment, at least 450 mg of mannitol is used for preparing a single dosage of the orally dispersible/disintegrable pharmaceutical composition of the present disclosure. This matrix formulation is further milled using a sieve of 20/30 mesh or 30/40 mesh to obtain granules of the orally dispersible/disintegrable pharmaceutical composition of the present disclosure with nanoparticles of cholecalciferol encapsulated inside the PEG and mannitol. In an embodiment, a variety of flavoring agents may be added to the composition and pressed to form an orally disintegrating tablet form by conventional mechanisms. In yet another embodiment, the formulated composition is further used in combination with other pharmaceutically active ingredients to obtain the orally dispersible/disintegrable solid dosage forms.
[0023] The formulated orally dispersible/disintegrable pharmaceutical composition when placed on tongue, the mannitol and the PEG gets dissolved rapidly within few seconds increasing the dissolution and bio availability of the cholecalciferol. The bioavailability of the orally dispersible/disintegrable pharmaceutical composition of the present disclosure is 90-95% when compared to that of the conventional solid and liquid dosage forms used for cholecalciferol.
[0024] FIG. 4 is a table illustrating an optimum composition for preparing the orally dispersible/disintegrable sachets and/or pouches of cholecalciferol in an embodiment of the present disclosure. As shown there, an optimum quantity of the components required for preparing a dosage form of at least 500 mg total weight (460) of the sachet or pouch or orally dispersible/disintegrable sachet/pouch comprises 50 mcg (appx) of cholecalciferol (410), 25 mg of PEG (420), 0.006 mg of propylene glycol (430), 454.994 mg of mannitol (440) and optionally 20 mg of a flavoring agent (450). Further, the optimal quantity of the components required to prepare at least 800 orally dispersible/disintegrable pouches/sachets of each 500 mg comprises 40 mg of cholecalciferol (410), 20 gm of PEG (420), 4.800 mg of propylene glycol (430), 363.9952 gm of mannitol (440) and optionally 16 gm of the flavoring agent (450). In an embodiment, the flavoring agent comprises flavor grape.
[0025] In an embodiment, bioavailability of the cholecalciferol through oral drug delivery is well established and the present pharmaceutical composition comprising granules/ orally disintegrating tablets are in line with the established studies.
[0026] FIG. 5 is a table illustrating an optimum composition for preparing the orally dispersible/disintegrable tablets of cholecalciferol in an embodiment of the present disclosure. The optimum composition for preparing an orally dispersible/disintegrable tablet with at least 65 mg of total weight (560) requires 50 mcg (appx) of cholecalciferol (510), 25 mg of PEG (520), 0.006 mg of propylene glycol (530), 65 mg of mannitol (540) and optionally 20 mg of a flavoring agent (550). Further, the optimum quantity of the components required for preparing at least 800 orally dispersible/disintegrable tablets of each 65 mg comprises 40 mg of cholecalciferol (510), 20 gm of PEG (520), 4.800 mg of propylene glycol (530), 52 gm of mannitol (540) and optionally 16 gm of the flavoring agent (550).
[0027] FIG. 6A and 6B are the schematic drawings illustrating the disintegration of the cholecalciferol in oral cavity by administering the tablets and sachets/pouches of the present disclosure. As shown there, the orally disintegrable tablet (610) or the orally disintegrable sachet (640) comprising the orally disintegrable pharmaceutical composition in powder form of the present disclosure is placed on the tongue or entered into the oral cavity wherein the orally disintegrable pharmaceutical composition gets dispersed immediately and disintegrates within a fraction of seconds after getting in contact with saliva (620). The disintegrated pharmaceutical composition thus completely gets absorbed into the oral mucosa (630) and increases the bioavailability of the cholecalciferol unlike the conventional mechanism of its absorption in the intestine. The orally disintegrable pharmaceutical composition for cholecalciferol of the present disclosure may be used in solid, liquid or semi-solid dosage forms such as tablets, capsules, beverages, drops, solutions, suspensions, lozenges, gums and chewing gums, topical applications such as gels, creams, patches, or nasal drug delivery.
[0028] While various embodiments of the present disclosure have been described above, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of the present disclosure should not be limited by any of the above-discussed embodiments, but should be defined only in accordance with the following claims and their equivalents.

CLAIMS
I/We Claim,
1. An orally disintegrable pharmaceutical composition for rapid release and increased bioavailability of a drug comprising:
a cholecalciferol (410) that acts as an active ingredient of the drug;
a propylene glycol (430) to stabilize the active ingredient;
a polyethylene glycol (PEG) (420) as an excipient of the drug; and
a mannitol (440) to provide a matrix for encapsulating the active ingredient, stabilizer and the drug excipient, wherein the cholecalciferol is dispersed as nano-particles of size 300 nm within the matrix and gets released by rapid dissolution of the PEG and the mannitol when administered orally.
2. The orally disintegrable pharmaceutical composition as claimed in claim 1, wherein the mannitol is blended with a flavouring agent (450) optionally to provide a flavour to the composition for oral administration.
3. The orally disintegrable pharmaceutical composition as claimed in claim 2, wherein the composition for a single dosage form of 500 mg comprises at least 50 mcg of the cholecalciferol, 0.006 mg of the propylene glycol, 25 mg of the PEG, 454.994 mg of the mannitol and 20 mg of the flavouring agent.
4. The orally disintegrable pharmaceutical composition as claimed in claim 3, wherein the bioavailability of the cholecalciferol is 90-95% when administered orally.
5. A method of preparing an orally dispersible pharmaceutical composition for cholecalciferol comprising:
taking cholecalciferol (310) as an active ingredient;
adding propylene glycol (320) as a stabilizing agent;
adding molten form of polyethylene glycol (PEG) (330) as an excipient;
ultrasonicating the mixture (340) and crushing it before condensation to obtain a plurality of nanoparticles of cholecalciferol; and
adding mannitol (350) to form a primary matrix for encapsulating the cholecalciferol, wherein the plurality of nanoparticles of the cholecalciferol are of size 300 nm and are dispersed uniformly within the primary matrix.
6. The method as claimed in claim 5, wherein the ultrasonication is performed at an ultrasonic frequency of 50000 watts for at least 120 seconds.
7. The method as claimed in claim 6, wherein the primary matrix and the PEG gets dissolved rapidly when they get in contact with a body fluid thereby releasing the cholecalciferol exhibiting increased bioavailability inside a human body.
8. A method, system and apparatus providing one or more features as described in the paragraphs of this specification.

Date: 27-03-2019 Signature…………………………

A METHOD AND ORALLY DISINTEGRABLE PHARMACEUTICAL COMPOSITION FOR CHOLECALCIFEROL
ABSTRACT
An orally disintegrable pharmaceutical composition for rapid release and increased bioavailability of a drug comprising a cholecalciferol (410) that acts as an active ingredient of the drug, a propylene glycol (430) to stabilize the active ingredient, a polyethylene glycol (PEG) (420) as an excipient of the drug, and a mannitol (440) to provide a matrix for encapsulating the active ingredient, stabilizer and the drug excipient, wherein the cholecalciferol is dispersed as nanoparticles of size 300 nm within the matrix and gets released by rapid dissolution of the PEG and the mannitol when administered orally. In an embodiment, the mannitol is blended with a flavouring agent (450) and the pharmaceutical composition for a single dosage form of 500 mg comprises at least 50 mcg of the cholecalciferol, 0.006 mg of the propylene glycol, 25 mg of the PEG, 454.994 mg of the mannitol and 20 mg of the flavouring agent.