DESC:FIELD OF INVENTION:
The present invention related to an orodispersible formulation more particularly to orodispersible tablet comprising Dydrogesterone and pharmaceutically acceptable salts thereof. The orodispersible tablet provides better patient compliance and rapid onset of action.
BACKGROUND:
Dydrogesterone is a synthetic hormone which have similar activity as that of natural hormone progesterone therefore it acts as a selective progesterone receptor agonist. Since dydrogesterone structurally and pharmacologically similar to natural progesterone, it is often used to treat progesterone deficiency. It helps in maintaining of pregnancy and in normal shedding of endometrial lining during menstrual period, thus it is indicated for irregular menstrual cycle, infertility, recurrent miscarriages and has no effect on ovulation process. Dydrogesterone is clinically approved for 40 years and found to be safe and have better tolerability profile. Oral Dydrogestrone is marketed as DUPHASTON which is available in 10 mg film coated oral tablets.
DUPHASTON is available in immediate release tablet dosage form which is indicated where progesterone supplement is needed such as endometriosis, irregular menstrual cycle, dysmenorrhoea, Infertility as a result of corpus luteum insufficiency, threatened abortion, Habitual abortion, dysfunctional uterine bleeding, secondary amenorrhoea and pre-menstrual syndrome. As the dosage form needs to be swallowed and patients should be able to perform the action of swallowing correctly. However, in swallowing may not be convenient for the patients who have hard time in swallowing, this condition is also known as Dysphagia. Thus, there is a need of dosage form which is easy to administer and doesn’t required swallowing and doesn’t required water and hence can be easily administered to the patients.
Orodispersible dosage form is a novel drug delivery system alternative to conventional oral solid dosage form which are formulated to disintegrate in mouth without the need of water. orodispersible tablets (ODT) can be easily administered to Dysphagia patients, pediatric and geriatric patients which provides rapid disintegration of tablet when came in contact with saliva. Orodispersible dosage form also provide faster onset of action and improved bioavailability as when medication is absorbed through oromucusal tissues and other pregastric areas, patients experience increased bioavailability and faster absorption of the medication. The medication absorbed in the mouth enters the bloodstream more quickly, making orally disintegrating tablets an ideal drug delivery for Dydrogesterone due to their superior bioavailability, faster pregastric absorption and higher rates of patient compliance by considering highly variability of this molecule & pre-systemic metabolism. Also considering the most targeted population of women its easily acceptable dosage forms due to palatable, sweet & flavour in taste and patient doesn’t required water to ingest orally disintegrating tablets and thus can be valuable for patients who travel frequently or need to take the medication in situations where they may not always have water on hand.
Thus, there remains a need in art for alternative formulations of Dydrogesterone or a pharmaceutically acceptable salt thereof who have difficulty in swallowing and provide rapid onset of actions which provide immediate pharmacological actions
SUMMARY OF THE INVENTION:
The present invention provides an oral dispersible formulation comprising effective amount of Dydrogesterone or its pharmaceutically acceptable salts thereof which disperse after administration direct to mouth or disperse in aqueous phase for example water before administration.
In another embodiment oral dispersible formulation is an oral dispersible tablet comprising effective amount of Dydrogesterone or its pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients.
In one embodiment the present invention provides an oral dispersible tablet which achieve disintegration within less than 3 minutes when taken by mouth or disperse in aqueous phase for example water before administration.
DETAILED DESCRIPTION OF THE INVENTION:
The following paragraphs detail various embodiments of the present invention. For the avoidance of doubt, it is specifically intended that any particular feature(s) described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). In other words, it is explicitly intended that the features described below individually in each paragraph (or part thereof) represent important aspects of the invention that may be taken in isolation and combined with other important aspects of the invention described elsewhere within this specification as a whole, and including the examples. The skilled person will appreciate that the invention extends to such combinations of features and that these have not been recited in detail here in the interests of brevity.
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
As used herein, the term "dispersible tablet formulation" or “Orodispersible” refers to a tablet which disperses in aqueous phase, for example water, before administration or a tablet which disperses after administration direct to mouth. Typically, dispersible tablets are solid pharmaceutical forms which are defined by their rate of disintegration in water and the uniformity of dispersion of the particles into which they disintegrate.
By "disintegration time" is meant the time that needs the dispersible tablet to disintegrate in water at room temperature in a disintegration time device.
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 present invention relates to novel drug delivery system comprising Dydrogesterone and pharmaceutical acceptable salts thereof and process of manufacturing thereof.
The present invention provides a dispersible formulation comprising an effective amount of Dydrogesterone or its pharmaceutically acceptable salts thereof.
In an embodiment the present invention provides a dispersible formulation in form of tablet, granules or powder wherein tablet form is being preferred.
The dispersible tablet comprising Dydrogesterone can be produced by conventional methods such as direct compression, direct mixing, wet granulation, dry granulation, fluid bed granulation, spray granulation.
In another embodiment the present invention provides an Orodispersible tablet comprising an effective amount of Dydrogesterone or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient or carrier.
In one embodiment the orodispersible tablet comprises 5 to 20% w/w of Dydrogesterone.
The Dydrogesterone may be in free form or in form of an ester, a salt, a hydrate, a solvate, a polymorph, an isomer or other pharmaceutically acceptable forms.
The pharmaceutically acceptable excipient or carrier for the preparation of dispersible tablet of the present invention can be selected from disintegrant, binder, diluent, glidant, anti- adherent, lubricant, flavouring agents, antioxidants, sweetening agents or buffering agents.
The essential ingredients, which impart the above desired properties to the dispersible tablets, are disintegrants. In the sense used in this invention they are agents, which imbibe water making rapid swelling and quick disintegration possible. The disintegrants used in the present invention are selected, but not limited, from the group comprising of corn or potato starch or modified starches (sodium carboxymethyl starch etc.), microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose (e.g. Ac-di-sol), cross-linked povidone and ion exchange resins such as Polacrilin potassium.
In one embodiment the disintegrant is Polacrilin potassium present in an amount ranging from 5 to 20% w/w of Polacrilin potassium as disintegrant.
In a preferred embodiment disintegrant is crospovidone present in an amount ranging from 10-50 mg.
Examples of binders that can be used in the present invention are for example hydroxypropylmethyl cellulose (Hypromellose), polyvinylpyrrolidone, polyethylene glycol, and the like; water-insoluble polymers, for example, ethyl cellulose, polyvinyl chloride, aminoalkyl and the like; and enteric polymers, for example, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer L, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxyvinyl polymer or combination thereof.
In one embodiment the preferred binder is hydroxypropylmethyl cellulose present in an amount ranging from 0.5 to 10% w/w.
In a preferred embodiment binder is hydroxypropylmethyl cellulose (hypromellose) present in an amount ranging from 2 to 10 mg.
Examples of lubricant that can be used in the present invention are adipic acid, aluminium stearate, calcium stearate, cethyl alcohol, fumaric acid, glyceryl monostearate, glyceryl palmitostearate, glyceryl tripalmitate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulphate, magnesium stearate, mineral oil, myristic acid, myristic alcohol, palmitic acid, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, stearyl alcohol, talc, triglycerides, zinc stearate and the like.
In on embodiment the preferred lubricant is magnesium stearate present in an amount ranging from 0.5 to 10% w/w.
Examples of Glidant that can be used in the present invention are colloidal silicon dioxide, magnesium trisilicate, talcum, powdered cellulose, starch, tribasic calcium phosphate, calcium stearate, glycerylbehenate, glycerylmonostearate, magnesium laurylsulfate, magnesium stearate, polyethyleneglycol, potassium benzonate, sodium stearate, sodium stearyl fumarate, stearic acid or combination thereof.
In on embodiment the preferred glidant is Talc present in an amount ranging from 0.5 to 10% w/w.
Examples of fillers/diluents that can be used in the present invention are acacia, alginic acid, cellulose, dextrin, dextrates, sucrose, tylose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, gelatin, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, lactose, sucrose, glucose, mannitol, sorbitol, microcrystalline cellulose, pectin, polyacrylates, cellulose acetate, hydroxypropylmethyl cellulose, calcium carbonate, calcium carboxy methylcellulose, Colloidal silicon dioxide, Talc, Magnesium stearate and others including combinations thereof.
In one embodiment the preferred diluent is mannitol present in an amount ranging from 10 to 60% w/w.
In a preferred embodiment diluent is Mannitol present in an amount ranging of 50-150 mg.
The dispersible tablet of the present invention preferably comprises Dydrogesterone in amount ranging from 5-30 mg more preferably 10 mg.
The sweetener or sweetening agent provides the sweetness to the dosage form and include but are not limited to sorbitol, dextrose, sodium saccharin, glucose, sucralose, trehalose, fructose, xylose, dextrose, mannitol, xylitol, aspartame or mixtures thereof. Preferred sweeteners are sodium saccharin or sorbitol.
In one embodiment the sweetening agent is Aspartame present in an amount of 0.05 to 1% w/w.
In a preferred embodiment sweetening agent is Aspartame present in an amount ranging from 0.05 to 5 mg.
In a present invention the present invention provides a method of treatment of disorders or conditions associated with progesterone deficiency more preferably for the treatment of endometriosis, irregular menstrual cycle, dysmenorrhoea, Infertility as a result of corpus luteum insufficiency, threatened abortion, Habitual abortion, dysfunctional uterine bleeding, secondary amenorrhoea and pre-menstrual syndrome
The orodispersible tablet of the present invention is an alternative to the conventional oral dosage form favorable for patients who have difficulty in swallowing solid dosage forms and provides rapid onset of action and provides immediate relief from endometriosis, irregular menstrual cycle, dysmenorrhoea, Infertility as a result of corpus luteum insufficiency, threatened abortion, Habitual abortion, dysfunctional uterine bleeding, secondary amenorrhoea, pre-menstrual syndrome or other progesterone related deficiency.
In another embodiment the present invention provides a dispersible tablet which can be dispersed in aqueous media such as water before administration or can directly administered through mouth where the tablet disintegrates in contact with saliva which provides rapid onset of action and is an effective solution for immediate relief from progesterone related deficiency.
The dispersible tablet formulations of the invention are typically administered once per day or as needed by the patient.
The disintegration time of the dispersible tablet of present invention is not more than 5 minutes more preferably disintegration time is less than 3 minutes.
In one embodiment the orodispersible tablet comprising:
i. 5 to 20% w/w of Dydrogesterone and;
ii. 10 to 60% w/w of diluent and;
iii. 5 to 20% w/w of Disintegrant and;
iv. 0.5 to 10% w/w of binder and;
v. 0.5 to 10% w/w of lubricant and
vi. 0.05 to 1% of sweetener
In another embodiment the present invention provides orodispersible tablet comprising:
i. 5 to 20% w/w of Dydrogesterone and;
ii. 10 to 60% w/w of Mannitol as diluent and;
iii. 5 to 20% w/w of Polacrilin potassium as Disintegrant and;
iv. 0.5 to 10% w/w of hydroxypropyl methyl cellulose (HPMC) as binder and;
v. 0.5 to 10% w/w of magnesium stearate as lubricant and
vi. 0.05 to 1% of Aspartame as sweetener
The present invention provides orodispersible tablet comprising:
i. 7.14% w/w of Dydrogesterone and;
ii. 10 to 60% w/w of Mannitol as diluent and;
iii. 1.79% of Hydroxypropy methyl cellulose as binder and;
iv. 7.14% w/w of Polacrilin potassium as disintegrant and;
v. 1.07% w/w of magnesium stearate as lubricant and;
vi. 0.57% w/w of Aspartame as sweetener
In an embodiment the present invention provides an orodispersible tablets comprising:
i. 10 mg Dydrogesterone as an active ingredient and
ii. 103 mg Mannitol as diluent and;
iii. 20 mg Crospovidone as disintegrant and;
iv. 3 mg hypromellose as binder and
v. 0.5 mg Aspartame as sweetening agent and;
One or more pharmaceutically acceptable excipients such as flavouring agent, glidant and lubricant.
According to all these embodiments, the below given formulations can be used in the pharmaceutical composition subjected to the invention. These examples are not limiting the scope of the present invention and should be considered under the light of the foregoing detailed disclosure.
In an embodiment the present invention provides method of manufacturing orodispersible tablet wherein the method comprises following steps:
1. Weigh all ingredients accurately in separate polybag
2. Co-sift the Dydrogesterone and half quantity of Mannitol and Kyron T314 through #40 sieve. Half quantity of mannitol was used for rinsing of sieve and sieve stand.
3. Dry mixing of powder blend of step 1 was transfer in RMG for 10 minutes at 100 rpm.
4. Prepare binder solution by dissolving HPMC E5 in required qty. of purified water under stirring to form clear solution.
5. Powder blend of step 3 was granulated by using prepared binder solution i.e. step 4 in RMG till granulation end point is achieved. Note down the total water qty. used.
6. Dry the wet granules from step 5 in FBD at inlet temperature 50°C±5°C till the % LOD reached.
7. Dried granules from step 6 was sized by sifting through 30# sieve.
8. Sifted granules from step 7 was blended with Mannitol, Talc, Kyron T314, Aspartame and Strawberry flavor (Previously sifted through 40# sieve) mixed in double cone blender for 10 min. at suitable rpm.
9. Lubricate the blend from step 8 with Magnesium stearate (Previously sifted through 60# sieve) was mixed in double cone blender for 5 min. at suitable rpm.
10. Compress the Lubricated blend from step 9 into tablets by using suitable punches.
The following examples further exemplify the invention and are not intended to limit the scope of the invention.
Example-1 Dydrogesterone Orodispersible Tablet
Sr.No. Name of Ingredient % w/w mg/tablet Excipients role
Dry-Mix
1. Dydrogesterone 7.14 10.00 Active agent
2. Mannitol 59.29 83.00 Diluent
3. Polacrilin potassium (Kyron T314) 7.14 10.00 Disintegrant
Binder Solution
4. HydroxyPropyl methyl cellulose (E-5) 1.79 2.50 binder
5. Purified Water q.s. q.s. Granulating fluid
Pre-lubrication
6. Talc 1.48 2.00 Glidant
7. Mannitol 14.28 20.00 Diluent
8. Polacrilin potassium (Kyron T314) 7.14 10.00 Disintegrant
9. Aspartame 0.57 0.80 Sweetener
Lubrication
10. Strawberry flavor 0.14 0.20 Flavour
11. Magnesium Stearate 1.07 1.50 Lubricant

Process of manufacturing:
1. Weigh all ingredients accurately in separate polybag
2. Co-sift the Dydrogesterone and half quantity of Mannitol and Kyron T314 through #40 sieve. Half quantity of mannitol was used for rinsing of sieve and sieve stand.
3. Dry mixing of powder blend of step 1 was transfer in RMG for 10 minutes at 100 rpm.
4. Prepare binder solution by dissolving HPMC E5 in required qty. of purified water under stirring to form clear solution.
5. Powder blend of step 3 was granulated by using prepared binder solution i.e. step 4 in RMG till granulation end point is achieved. Note down the total water qty. used.
6. Dry the wet granules from step 5 in FBD at inlet temperature 50°C±5°C till the % LOD reached.
7. Dried granules from step 6 was sized by sifting through 30# sieve.
8. Sifted granules from step 7 was blended with Mannitol, Talc, Kyron T314, Aspartame and Strawberry flavor (Previously sifted through 40# sieve) mixed in double cone blender for 10 min. at suitable rpm.
9. Lubricate the blend from step 8 with Magnesium stearate (Previously sifted through 60# sieve) was mixed in double cone blender for 5 min. at suitable rpm.
10. Compress the Lubricated blend from step 9 into tablets by using suitable punches.

Example-2:
The tablets obtained from example-1 was kept at different temperature and relative humidity for 3 months where different studies such as assay, disintegration, impurity and dissolution studies were performed.
Sr.
No Name of Test Specification Result
Initial 40 °C/75 % RH 30°C/75 % RH 30°C/65 % RH 25 °C/60 % RH
1 M 3 M 3 M 3 M 3 M
1. Description White to off white, round, biconvex, film tablets, Breakline on one side and Plain on other side
2. Assay 90 to 110% 99.6 98.7 98.2 98.8 98.7 98.8
3. Water By KF % Not more than 9.0%. 5.8 6.6 6.9 7.2 6.4 6.2
4. Disintegration Time (min :Sec) NMT 30 Min. 00:20-00:32 01:15-01:58 01:30-02:00 01:28-01:45 01:15-01:38 01:01-01:12
5. Related Substances by HPLC (%)
Dydrogesterone Impurity-A NMT 0.3% 0.07 0.06 0.06 0.05 0.06 0.05
Dydrogesterone Impurity-B NMT 0.15% ND ND 0.01 0.01 0.01 0.01
Dydrogesterone Impurity-C NMT 0.3% 0.03 0.04 0.04 0.04 0.04 0.03
Any other individual Impurity NMT 0.2% 0.02 0.02 0.02 0.02 0.02 0.02
Total Impurities (%) NMT 1.0% 0.12 0.12 0.15 0.14 0.15 0.13
6. Dissolution
Dissolution Condition Dissolution Medium: 0.3% SLS in Water, Volume: 500 mL, Apparatus: Paddle, RPM:100
Not Less Than 75% (Q) of labelled amount of Dydrogesterone must dissolved. % Drug Release
95 97 93 92 91 92
,CLAIMS:1. An orodispersible formulation comprising Dydrogesterone in an amount of from 5 to 20% w/w.
2. An orodispersible formulation as claimed in claim 1 wherein the formulation is tablet.
3. An orodispersible tablet as claimed in claim 2, wherein the tablet further comprises excipients is selected from diluent, binder, disintegrating agent, lubricant, sweetening agent and glidant or combinations thereof.
4. An orodispersible tablet as claimed in claim 2, wherein the atleast one diluent is selected from the group consisting of acacia, alginic acid, cellulose, dextrin, dextrates, sucrose, tylose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, gelatin, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, lactose, sucrose, glucose, mannitol, sorbitol, microcrystalline cellulose, pectin, polyacrylates, cellulose acetate, hydroxypropylmethyl cellulose, calcium carbonate, calcium carboxy methylcellulose, colloidal silicon dioxide, talc, Magnesium stearate and others including combinations thereof.
5. An orodispersible tablet as claimed in claim 2, wherein binder is selected from hydroxypropylmethyl cellulose (Hypromellose), polyvinylpyrrolidone, polyethylene glycol, and the like; water-insoluble polymers, for example, ethyl cellulose, polyvinyl chloride, aminoalkyl and the like; and enteric polymers, for example, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer L, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxyvinyl polymer
6. An orodispersible tablet as claimed in claim 2, wherein disintegrating agent is hydroxypropylmethyl cellulose (Hypromellose), polyvinylpyrrolidone, polyethylene glycol, and the like; water-insoluble polymers, for example, ethyl cellulose, polyvinyl chloride, aminoalkyl and the like; and enteric polymers, for example, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer L, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxyvinyl polymer
7. An orodispersible tablet as claimed in claim 2, wherein lubricant is adipic acid, aluminium stearate, calcium stearate, cethyl alcohol, fumaric acid, glyceryl monostearate, glyceryl palmitostearate, glyceryl tripalmitate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulphate, magnesium stearate, mineral oil, myristic acid, myristic alcohol, palmitic acid, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, stearyl alcohol, talc, triglycerides, zinc stearate and the like.
8. An orodispersible tablet as claimed in claim 2, wherein sweetening agent is sorbitol, dextrose, sodium saccharin, glucose, sucralose, trehalose, fructose, xylose, dextrose, mannitol, xylitol, aspartame
9. An orodispersible tablet as claimed in claim 2, wherein glidant is colloidal silicon dioxide, magnesium trisilicate, talcum, powdered cellulose, starch, tribasic calcium phosphate, calcium stearate, glycerylbehenate, glycerylmonostearate, magnesium laurylsulfate, magnesium stearate, polyethyleneglycol, potassium benzonate, sodium stearate, sodium stearyl fumarate, stearic acid.
10. An orodispersible tablet as claimed in claim 2-9, wherein tablet comprises:
i. 5 to 20% w/w of Dydrogesterone and;
ii. 10 to 60% w/w of diluent and;
iii. 5 to 20% w/w of Disintegrant and;
iv. 0.5 to 10% w/w of binder and;
v. 0.5 to 10% w/w of lubricant and
vi. 0.05 to 1% of sweetener