A direct compressed orodispersible tablet of desmopressin

Abstract

The present invention relates to a direct compressed orodispersible tablet comprising desmopressin acetate and at least one pharmaceutically acceptable excipient. Particularly, the present invention relates to a direct compressed orodispersible tablet which is storage stable, disintegrates rapidly in the oral cavity and exhibits bioequivalence when compared to marketed lyophilized product Minirin® Melt. The invention further relates to a process for the preparation of the direct compressed orodispersible tablet of desmopressin acetate.

Description

[0001] A DIRECT COMPRESSED ORODISPERSIBLE TABLET OF DESMOPRESSIN

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a direct compressed orodispersible tablet comprising desmopressin acetate and at least one pharmaceutically acceptable excipient. Particularly, the present invention relates to a direct compressed orodispersible tablet which is storage stable, disintegrates rapidly in the oral cavity and exhibits bioequivalence when compared to marketed lyophilized product Minirin® Melt. The invention further relates to a process for the preparation of the direct compressed orodispersible tablet of desmopressin acetate.

[0004] BACKGROUND OF THE INVENTION

[0005] Desmopressin is chemically known as 1 -(3-Mercaptopropanoic acid)-8-D-arginine vasopressin (I).

[0006] Desmopressin is a synthetic derivative of the natural human hormone arginine vasopressin, also known as the antidiuretic hormone (ADH). This peptide consists of nine amino acids and is commercially available in both tablet and nasal spray forms, typically prescribed for conditions such as voiding postponement, incontinence, primary nocturnal enuresis (PNE), and nocturia and central diabetes insipidus.

[0007] The sublingual formulation of Desmopressin acetate is marketed as Minirin® Melt by Ferring in Europe since 2005. The marketed products are approved in the forms of 60 mcg, 120 mcg, 240 mcg. The Minirin® Melt is prepared by lyophilization process to attain the desired rapid disintegration.

[0008] EP1501534 B1 discloses an orodispersible pharmaceutical dosage form of desmopressin acetate prepared by freeze drying (lyophilization) process, which disintegrates in the mouth within 10 seconds.

[0009] It is known that in lyophilization or freeze drying, removal of solvent from a drug solution provides highly porous tablets that absorb water and dissolve rapidly. It maintains drug stability by working at low temperatures. However, major disadvantages of lyophilization are costly, time consuming, challenging to scale up, and may result in fragile tablets with poor stability and mechanical properties, and often requiring special packaging.

[0010] To overcome the problem of lyophilization, another favorable technology for low drug concentration containing product is wet granulation which is preferred to provide pharmaceutically acceptable content uniformity of the drug. The following patents / applications disclose wet granulation process for desmopressin acetate formulations.

[0011] EP1530967 B1 disclose tablet formulation of desmopressin, prepared by wet granulation, wherein said solid dosage form contains an agent that provides a pH in the range of from 3.0 to 6.2 as measured when 1 g of said solid dosage form is slurred in 2 ml of water at 25°C.

[0012] EP1699437 B1 discloses a method for the preparation of a solid dosage form of desmopressin comprising granulating desmopressin or a pharmaceutically acceptable salt thereof and at least one excipient, carrier or diluent or mixture thereof in a fluid bed granulation apparatus, wherein the resulting desmopressin containing granulate is suitable for compression to a pharmaceutically acceptable tablet.

[0013] IN202121012429 discloses a solid dosage form of desmopressin, or its pharmaceutically acceptable salt prepared by wet granulation.

[0014] TR2021 / 015608 discloses a solid dosage form of desmopressin or its pharmaceutically acceptable salt, and citric acid prepared by wet granulation. It is known that the wet granulation process involves mixing powders with a liquid binder to form granules. This process can be used to improve compressibility, and content uniformity especially when the drug used in the low concentration. However, the disadvantages of wet granulation are time-consuming, requires specialized and costly equipment, can lead to issues like over-wetting and inconsistent granule size, and wet granules are hygroscopic affecting stability of the formulation as compared to direct compression.

[0015] Therefore, there still exists need to provide a stable orodispersible tablet of desmopressin with suitable excipient(s) that provides favourable disintegration time and improved dissolution rate, and thus provide desired bioavailability, which can be prepared by an economically viable, robust & simple process that is suitable for use on a commercial scale.

[0016] The inventors of the present invention have surprisingly found that a direct compressed orodispersible tablet comprising desmopressin acetate and a pharmaceutically acceptable excipient not only provides storage stable composition but also shows similar impurity profile and bioequivalence when compared to the reference product Minirin® Melt lyophilized tablets.

[0017] OBJECT OF THE INVENTION

[0018] The main object of the present invention is to provide a direct compressed orodispersible tablet comprising desmopressin acetate and a pharmaceutically acceptable excipient, which is bioequivalent when compared to marketed lyophilized product Minirin® Melt.

[0019] Another object of the present invention is to provide a direct compressed orodispersible tablet comprising desmopressin acetate and a pharmaceutically acceptable excipient that disintegrates within 3 to 30 seconds.

[0020] Another object of the present invention is to provide a direct compressed orodispersible tablet comprising desmopressin acetate and a pharmaceutically acceptable excipients which has a pleasant taste to the patient. Another object of the present invention is to provide a direct compressed orodispersible tablet comprising desmopressin acetate and pharmaceutically acceptable excipients, which is storage stable.

[0021] Another object of the invention is to provide a commercially scalable, cost effective, environment friendly, simple, and robust process for the preparation of a direct compressed orodispersible tablet comprising desmopressin acetate and pharmaceutically acceptable excipients.

[0022] SUMMARY OF THE INVENTION

[0023] In one aspect, the present invention provides a direct compressed orodispersible tablet comprising desmopressin acetate and a pharmaceutically acceptable excipient.

[0024] In another aspect, the present invention provides a direct compressed orodispersible tablet comprising: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of one or more of diluent; c. about 0.1 wt.% to 5 wt.% of one or more of stabilizing agent; d. about 5 wt.% to 20 wt.% of one or more of disintegrant; e. about 0.01 wt.% to 5 wt.% of one or more lubricant; f. about 0.01 wt.% to 3 wt.% of one or more sweetener; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0025] In another aspect, the present invention provides a direct compressed orodispersible tablet consisting essentially of: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of one or more of diluent; c. about 0.1 wt.% to 5 wt.% of one or more of stabilizing agent; d. about 5 wt.% to 20 wt.% of one or more of disintegrant; e. about 0.01 wt.% to 5 wt.% of one or more lubricant; f. about 0.01 wt.% to 3 wt.% of one or more sweetener; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0026] In another aspect, the present invention provides a non-lyophilized direct compressed orodispersible tablet comprising: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of one or more of diluent; c. about 0.1 wt.% to 5 wt.% of one or more of stabilizing agent; d. about 5 wt.% to 20 wt.% of one or more of disintegrant; e. about 0.01 wt.% to 5 wt.% of one or more lubricant; f. about 0.01 wt.% to 3 wt.% of one or more sweetener; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0027] In another aspect, the present invention provides a non-lyophilized direct compressed orodispersible tablet consisting essentially of: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of one or more of diluent; c. about 0.1 wt.% to 5 wt.% of one or more of stabilizing agent; d. about 5 wt.% to 20 wt.% of one or more of disintegrant; e. about 0.01 wt.% to 5 wt.% of one or more lubricant; f. about 0.01 wt.% to 3 wt.% of one or more sweetener; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0028] In another aspect, the present invention provides a direct compressed orodispersible tablet comprising: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide or mixture thereof; c. about 0.1 wt.% to 5 wt.% of citric acid; d. about 5 wt.% to 20 wt.% of crospovidone; e. about 0.01 wt.% to 5 wt.% of sodium stearyl fumarate; f. about 0.01 wt.% to 3 wt.% of sucralose; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0029] In another aspect, the present invention provides a direct compressed orodispersible tablet consisting essentially of: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide or mixture thereof; c. about 0.1 wt.% to 5 wt.% of citric acid; d. about 5 wt.% to 20 wt.% of crospovidone; e. about 0.01 wt.% to 5 wt.% of sodium stearyl fumarate; f. about 0.01 wt.% to 3 wt.% of sucralose; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0030] In another aspect, the present invention provides a non-lyophilized direct compressed orodispersible tablet comprising: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide or mixture thereof; c. about 0.1 wt.% to 5 wt.% of citric acid; d. about 5 wt.% to 20 wt.% of crospovidone; e. about 0.01 wt.% to 5 wt.% of sodium stearyl fumarate; f. about 0.01 wt.% to 3 wt.% of sucralose; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0031] In another aspect, the present invention provides a non-lyophilized direct compressed orodispersible tablet consisting essentially of: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide or mixture thereof; c. about 0.1 wt.% to 5 wt.% of citric acid; d. about 5 wt.% to 20 wt.% of crospovidone; e. about 0.01 wt.% to 5 wt.% of sodium stearyl fumarate; f. about 0.01 wt.% to 3 wt.% of sucralose; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0032] In another aspect, the present invention provides a direct compressed orodispersible tablet that disintegrates within 3 to 30 seconds.

[0033] In another aspect, the present invention provides a direct compressed orodispersible tablet which remains stable after storage at 40°C 1 75% RH for at least 1 month.

[0034] In another aspect, the present invention relates to provides a direct compressed orodispersible tablet comprising desmopressin acetate and a pharmaceutically acceptable excipient, which is prepared without using any granulation or lyophilization process.

[0035] In another aspect, the present invention provides a commercially scalable, cost effective, environment friendly, simple and robust process for the preparation of a direct compressed orodispersible tablet comprising desmopressin acetate and pharmaceutically acceptable excipients.

[0036] In another aspect, the present invention provides a process for preparation of the orodispersible tablet comprises following steps: a. preparing dry mix blend of desmopressin acetate, at least one stabilizing agent and at least one diluent, b. adding mixture of at least one sweetener, at least one flavoring agent and at least one diluent to the dry mix blend obtained in step-a, c. adding mixture of at least one diluent and at least one disintegrating agent to the mixture obtained in step-b, d. adding lubricating agent to the mixture obtained in step-c and blending them to obtain a homogenous powder mixture, and e. compressing the powder mixture obtained in step-d to form tablets. In another aspect, the present invention provides a process for preparation of the orodispersible tablet comprises of following steps: a. preparing dry mix blend of desmopressin acetate, citric acid and mannitol, b. adding mixture of sucralose, at least one flavoring agent, mannitol, silicified microcrystalline cellulose, to the dry mix blend obtained in step-a, c. adding mixture of mannitol and crospovidone to the mixture obtained in step-b, d. adding sodium stearyl fumarate to the mixture obtained in step-c and blending them to obtain a homogenous powder mixture, and e. compressing the powder mixture obtained in step-d to form tablets.

[0037] In another aspect, the present invention relates to orodispersible tablet comprising desmopressin acetate and pharmaceutically acceptable excipients for the prevention or treatment of incontinence, voiding postponement, primary nocturnal enuresis (PNE), nocturia or central diabetes insipidus.

[0038] The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

[0039] DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0040] The present invention will now be more specifically illustrated as hereunder.

[0041] The term “%”, “wt.%” or “%w / w” used in this specification means the percentage by the total weight of the composition unless otherwise stipulated.

[0042] The term "about" can indicate a difference of 10 percent of the value specified. Numerical ranges as used herein are meant to include every number and subset of numbers enclosed within that range, whether particularly disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. The phrase “orodispersible tablet” is a unique pharmaceutical dosage form designed to disintegrate or dissolve rapidly in the mouth, without the need for water or chewing. Specifically, the orodispersible tablet of present invention disintegrates within 3 to 30 seconds. Herein, orodispersible tablet, sublingual tablet or orally disintegrating tablet can be used interchangeably.

[0043] The phrase “direct compressed orodispersible tablet” refers to a tablet prepared by directly compressing a mixture of an active ingredient and excipient(s) without granulation or compaction. This method involves mixing the powdered active ingredient and excipient(s) simultaneously or sequentially and thoroughly then compressing the powder mixture directly into tablet form. Specifically, the direct compressed orodispersible tablet of the present invention is not prepared by lyophilization process.

[0044] The term "stable" or "stability" means that the pharmaceutical dosage form such as tablet is physically and chemically stable, whereas "chemically stable" means that the solid pharmaceutical dosage form when stored at 40°C I 75% RH for 3 months, degradation unknown impurity (single maximum impurity) and total impurities remain within ICH limit.

[0045] In one aspect of the present invention provides a direct compressed orodispersible tablet comprising desmopressin acetate and a pharmaceutically acceptable excipient, which is bioequivalent when compared to marketed lyophilized product Minirin® Melt.

[0046] The excipients to be used in accordance with the present invention are well known and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the orodispersible tablet, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients. The pharmaceutical excipient can be selected from diluent, stabilizing agents, disintegrant, lubricant, sweetener and flavoring agent.

[0047] In another aspect, the present invention provides a direct compressed orodispersible tablet comprising: a. about 0.01 wt% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of one or more of diluent; c. about 0.1 wt.% to 5 wt.% of one or more of stabilizing agent; d. about 5 wt.% to 20 wt.% of one or more of disintegrant; e. about 0.01 wt.% to 5 wt.% of one or more lubricant; f. about 0.01 wt.% to 3 wt.% of one or more sweetener; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0048] In another aspect, the present invention provides a direct compressed orodispersible tablet consisting essentially of: a. about 0.01 wt% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of one or more of diluent; c. about 0.1 wt.% to 5 wt.% of one or more of stabilizing agent; d. about 5 wt.% to 20 wt.% of one or more of disintegrant; e. about 0.01 wt.% to 5 wt.% of one or more lubricant; f. about 0.01 wt.% to 3 wt.% of one or more sweetener; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0049] In another aspect, the present invention provides a non-lyophilized direct compressed orodispersible tablet comprising: a. about 0.01 wt% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of one or more of diluent; c. about 0.1 wt.% to 5 wt.% of one or more of stabilizing agent; d. about 5 wt.% to 20 wt.% of one or more of disintegrant; e. about 0.01 wt.% to 5 wt.% of one or more lubricant; f. about 0.01 wt.% to 3 wt.% of one or more sweetener; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, h. wherein wt.% is based on the total weight of the orodispersible tablet.

[0050] In another aspect, the present invention provides a a non-lyophilized direct compressed orodispersible tablet consisting essentially of: a. about 0.01 wt% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of one or more of diluent; io c. about 0.1 wt.% to 5 wt.% of one or more of stabilizing agent; d. about 5 wt.% to 20 wt.% of one or more of disintegrant; e. about 0.01 wt.% to 5 wt.% of one or more lubricant; f. about 0.01 wt.% to 3 wt.% of one or more sweetener; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0051] Diluents includes, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide and mixtures thereof, preferably the diluent is mannitol (like Pearlitol®) and / or silicified microcrystalline cellulose (like PROSOLV® SMCC HD 90). The amount of diluent is preferably from about 50 wt.% to 90 wt.%, more preferably from about 70 wt.% to about 80 wt.% based on the total weight of the composition.

[0052] Stabilizing agents include, but are not limited to antioxidants, preservatives and chelating agents (such as citric acid (its hydrates or in anhydrous form) or EDTA). The stabilizing agent is selected from citric acid, tartaric acid, ascorbic acid and maleic acid or mixture thereof. Preferably, the stabilizing agent is citric acid anhydrous. These agents help prolong the shelf life, enhance texture, and maintain the quality of products. The amount of stabilizing agents is preferably from about 0.1 wt.% to 5 wt.%, more preferably from about 0.1 wt.% to 2 wt.% based on the total weight of the composition.

[0053] Disintegrant includes, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate and mixtures thereof. The amount of the disintegrant is preferably from 5 wt.% to about 20 wt.%, more preferably from 15 wt.% to 20 wt.% based on the total weight of the composition.

[0054] Suitable lubricants and / or glidants are selected from magnesium stearate, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, stearic acid, sodium stearyl fumarate, calcium stearate, zinc stearate, aluminum silicate, talc, colloidal silicon dioxide, sucrose esters of fatty acid, waxes, silica gel and mixtures thereof. The present invention comprises a lubricant in an amount of from about 0.01 wt.% to about 5 wt.%, preferably, 2 wt.% to about 5 wt.% based on the total weight of the composition.

[0055] Sweeteners are selected from lactose, mannitol, aspartame, sucralose, acesulfame potassium, cyclamate, saccharin and saccharin sodium are commonly used to mask bitterness and enhance palatability. Lactose and mannitol are natural sugar options, while aspartame, sucralose, acesulfame potassium, cyclamate, saccharin and saccharin sodium are artificial sweeteners. The present invention comprises a sweetener in an amount of from about 0.01 wt.% to about 3 wt.%, preferably, 0.05 wt.% to about 0.2 wt.% based on the total weight of the composition.

[0056] Flavoring agents are vital to enhance the taste and overall acceptability of the medication, especially for patients who may find the natural taste of active ingredients unpleasant. A variety of flavoring agents are used, including natural extracts and synthetic compounds. Flavoring agent such as cherry, grape, strawberry, orange, watermelon, banana, mint, citrus and vanilla or mixture thereof can be used for the present invention. Synthetic flavoring compounds like ethyl maltol and vanillin are also utilized to create specific tastes. These agents not only mask the inherent bitterness of some drugs but also contribute to improving patient adherence, ensuring that the medication is more palatable and easier to take, thereby enhancing the overall patient experience. The present invention comprises a flavoring agent in an amount of from about 0.01 wt.% to about 5 wt.%, preferably, 0.05 wt.% to about 0.2 wt.% based on the total weight of the composition.

[0057] In another aspect, the present invention provides a directly compressible orodispersible tablet comprising: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide or mixture thereof; c. about 0.1 wt.% to 5 wt.% of citric acid; d. about 5 wt.% to 20 wt.% of crospovidone; e. about 0.01 wt.% to 5 wt.% of sodium stearyl fumarate; f. about 0.01 wt.% to 3 wt.% of sucralose; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0058] In another aspect, the present invention provides a directly compressible orodispersible tablet consisting essentially of: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide or mixture thereof; c. about 0.1 wt.% to 5 wt.% of citric acid; d. about 5 wt.% to 20 wt.% of crospovidone; e. about 0.01 wt.% to 5 wt.% of sodium stearyl fumarate; f. about 0.01 wt.% to 3 wt.% of sucralose; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0059] In another aspect, the present invention provides a non-lyophilized directly compressible orodispersible tablet comprising: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide or mixture thereof; c. about 0.1 wt.% to 5 wt.% of citric acid; d. about 5 wt.% to 20 wt.% of crospovidone; e. about 0.01 wt.% to 5 wt.% of sodium stearyl fumarate; f. about 0.01 wt.% to 3 wt.% of sucralose; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0060] In another aspect, the present invention provides a non-lyophilized directly compressible orodispersible tablet consisting essentially of: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide or mixture thereof; c. about 0.1 wt.% to 5 wt.% of citric acid; d. about 5 wt.% to 20 wt.% of crospovidone; e. about 0.01 wt.% to 5 wt.% of sodium stearyl fumarate; f. about 0.01 wt.% to 3 wt.% of sucralose; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

[0061] In another aspect, the present invention provides a direct compressed orodispersible tablet comprising desmopressin acetate and a pharmaceutically acceptable excipient, which is prepared without any granulation or lyophilization process.

[0062] In another aspect, the direct compressed orodispersible desmopressin acetate tablet of the present invention shows equivalent dissolution profile to Minirin® Melt when dissolution tests were performed using standard dissolution media water (500ml, USP II (Paddle), 75rpm). The drug release was determined by using an HPLC method. Further, disintegration test, content uniformity test, assay and impurity analysis for the tablet is well within the capability of those skilled in the art.

[0063] In another aspect, the present invention provides a commercially scalable, cost effective, environment friendly, simple and robust process for the preparation of a direct compressed orodispersible tablet comprising desmopressin acetate and pharmaceutically acceptable excipients.

[0064] In another aspect, the present invention provides a process for preparation of the orodispersible tablet comprises of following steps: a. preparing dry mix blend of desmopressin acetate, at least one stabilizing agent and at least one diluent, b. adding mixture of at least one sweetener, at least one flavoring agent and at least one diluent to the dry mix blend obtained in step-a, c. adding mixture of at least one diluent and at least one disintegrating agent to the mixture obtained in step-b, d. adding lubricating agent to the mixture obtained in step-c and blending them to obtain a homogenous powder mixture, and e. compressing the powder mixture obtained in step-d to form tablets.

[0065] In another aspect, the present invention provides a process for preparation of the orodispersible tablet comprises of following steps: a. preparing dry mix blend of desmopressin acetate, citric acid and mannitol, b. adding mixture of sucralose, strawberry flavor, mannitol, silicified microcrystalline cellulose, to the dry mix blend obtained in step-a, c. adding mixture of mannitol and crospovidone to the mixture obtained in step-b, d. adding sodium stearyl fumarate to the mixture obtained in step-c and blending them to obtain a homogenous powder mixture, and e. compressing the powder mixture obtained in step-d to form tablets.

[0066] Moreover, the pharmaceutical composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.

[0067] The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.

[0068] Examples:

[0069] Example 1 : A directly compressible orodispersible tablet of desmopressin:

[0070] Table-1

[0071] * ~67 mcg / 133 mcg / 266 mcg Desmopressin acetate is equivalent to 60 mcg / 120 mcg / 240 mcg Desmopressin.

[0072] Process:

[0073] 1. desmopressin acetate, citric acid and mannitol (1.29 mg, 1.22 mg and 1.09 mg for 60 mcg, 120 mcg and 240 mcg of desmopressin respectively) were sifted through ASTM #35 mesh and mixed in blender to prepare dry mix (ASMT: American Standard Test Sieve Series).

[0074] 2. sucralose, strawberry flavor, mannitol (28 mg), silicified microcrystalline cellulose were sifted through ASTM #35 mesh, added to the dry mix blend obtained in step-1 and mixed in blender.

[0075] 3. mannitol (28 mg) and crospovidone were sifted through ASTM #35 mesh, added to the mixture obtained in step-2 and mixed in blender.

[0076] 4. sodium stearyl fumarate was sifted through ASTM # 60 mesh, added to the mixture obtained in step-3 and was blended to obtain a homogenous powder mixture.

[0077] 5. the powder mixture obtained in step-4 was compressed to tablets.

[0078] Example 2: Stability Result of 240mcg desmopressin acetate tablets of Example- 1

[0079] The tablets prepared in Example-1 were packed in Alu-Alu blister and stored for 1 month and 3 Months under conditions of 40°C I 75% RH. The results of performed stability testing are given herein below table- 2. Table-2

[0080] Table-2 shows that the direct compressed orodispersible tablets of the present invention are storage stable. Further, these tablets also have very good content uniformity. Example 3: Dissolution Profile of Example 1 and Minirin® Melt

[0081] Table-3

[0082] Dissolution of Example-1 and Minirin® Melt tablets were performed using dissolution Media-Water, 500ml, USP II (Paddle), RPM-75. The drug release was determined by using an HPLC method. The data summarized in Table-3 shows that Example-1 exhibits equivalent dissolution profile to Minirin® Melt.

[0083] Example 4: Bioavailability Data:

[0084] The formulation 240 mcg of Example-1 was subjected to bioequivalent study. The pharmacokinetic parameters evaluation includes evaluation of maximum concentration (Cmax) and area under the concentration-time curve from zero to the last measurable concentration (AUCo-t) for bioequivalence. The obtained data summarized in Table-4.

[0085] Table-4

[0086] The data summarized in Table-4 shows that Example-1 exhibits bioequivalence compared to Minirin® Melt.

[0087] The direct compressed orodispersible tablet of desmopressin acetate of the present invention not only provides stable composition but also provides tablets with good content uniformity and exhibits bioequivalence when compared to the reference product Minirin® Melt lyophilized tablets.

Claims

Claims:1 . A direct compressed orodispersible tablet comprising: a. about 0.01 wt.% to 5 wt.% of desmopressin acetate; b. about 50 wt.% to 90 wt.% of one or more of diluents; c. about 0.1 wt.% to about 5 wt.% of one or more of stabilizing agents; d. about 5 wt.% to 20 wt.% of one or more of disintegrants; e. about 0.01 wt.% to 5 wt.% of one or more lubricant; f. about 0.01 wt.% to 3 wt.% of one or more sweetener; and g. about 0.01 wt.% to 3 wt.% of one or more flavoring agent, wherein wt.% is based on the total weight of the orodispersible tablet.

2. The orodispersible tablet as claimed in claim 1 disintegrates within 3 to 30 seconds.

3. The orodispersible tablet as claimed in claim 1 , wherein diluent is selected from lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide and mixtures thereof.

4. The orodispersible tablet as claimed in claim 1 , wherein diluent is mixture of mannitol and silicified microcrystalline cellulose.

5. The orodispersible tablet as claimed in claim 1 , wherein stabilizing agent is selected from citric acid, tartaric acid, ascorbic acid, maleic acid and mixture thereof.

6. The orodispersible tablet as claimed in claim 1 , wherein disintegrating agent is selected from sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkylsubstituted hydroxypropyl cellulose, starch, pregelatinized starch, sodium alginate and mixtures thereof.

7. The orodispersible tablet as claimed in claim 1 , wherein lubricating agent is selected from magnesium stearate, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, stearic acid, sodium stearyl fumarate, sodium starch fumarate, calcium stearate, zinc stearate, aluminum silicate, talc, colloidal silicon dioxide, sucrose esters of fatty acid, waxes, silica gel and mixtures thereof.

8. The orodispersible tablet as claimed in claim 1 , wherein sweetener is selected from lactose, mannitol, aspartame, sucralose, acesulfame potassium, cyclamate, saccharin and saccharin sodium.

9. The orodispersible tablet as claimed in claim 1 , wherein flavoring agent is selected from selected from cherry, grape, strawberry, orange, watermelon, banana, mint, citrus, vanilla and mixtures thereof.

10. A process for the preparation of orodispersible tablet as claimed in claim 1 comprises of following steps: a. preparing dry mix blend of desmopressin acetate, at least one stabilizing agent and at least one diluent, b. adding mixture of at least one sweetener, at least one flavoring agent and at at least one diluent to the dry mix blend obtained in step-a, c. adding mixture of at least one diluent and at least one disintegrating agent to the mixture obtained in step-b, d. adding lubricating agent to the mixture obtained in step-c and blending them to obtain a homogenous powder mixture, and e. compressing the powder mixture obtained in step-d to form tablets.

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